@article{wang_li_shi_zhu_hu_dinh_cheng_2023, title={A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus}, volume={9}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.abo4100}, DOI={10.1126/sciadv.abo4100}, abstractNote={The circulating flu viruses merging with the ongoing COVID-19 pandemic raises a more severe threat that promotes the infectivity of SARS-CoV-2 associated with higher mortality rates. Here, we conjugated recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein onto inactivated influenza A virus (Flu) to develop a SARS-CoV-2 virus-like particle (VLP) vaccine with two-hit protection. This double-hit vaccine (Flu-RBD) not only induced protective immunities against SARS-CoV-2 but also remained functional as a flu vaccine. The Flu core improved the retention and distribution of Flu-RBD vaccine in the draining lymph nodes, with enhanced immunogenicity. In a hamster model of live SARS-CoV-2 infection, two doses of Flu-RBD efficiently protected animals against viral infection. Furthermore, Flu-RBD VLP elicited a strong neutralization activity against both SARS-CoV-2 Delta pseudovirus and wild-type influenza A H1N1 inactivated virus in mice. Overall, the Flu-RBD VLP vaccine is a promising candidate for combating COVID-19, influenza A, and coinfection.}, number={25}, journal={SCIENCE ADVANCES}, author={Wang, Zhenzhen and Li, Zhenhua and Shi, Weiwei and Zhu, Dashuai and Hu, Shiqi and Dinh, Phuong-Uyen C. and Cheng, Ke}, year={2023}, month={Jun} }
 @article{mei_li_wang_zhu_huang_hu_popowski_cheng_2023, title={An inhaled bioadhesive hydrogel to shield non-human primates from SARS-CoV-2 infection}, volume={2}, ISSN={1476-1122 1476-4660}, url={http://dx.doi.org/10.1038/s41563-023-01475-7}, DOI={10.1038/s41563-023-01475-7}, abstractNote={The surge of fast-spreading SARS-CoV-2 mutated variants highlights the need for fast, broad-spectrum strategies to counteract viral infections. In this work, we report a physical barrier against SARS-CoV-2 infection based on an inhalable bioadhesive hydrogel, named spherical hydrogel inhalation for enhanced lung defence (SHIELD). Conveniently delivered via a dry powder inhaler, SHIELD particles form a dense hydrogel network that coats the airway, enhancing the diffusional barrier properties and restricting virus penetration. SHIELD's protective effect is first demonstrated in mice against two SARS-CoV-2 pseudo-viruses with different mutated spike proteins. Strikingly, in African green monkeys, a single SHIELD inhalation provides protection for up to 8 hours, efficiently reducing infection by the SARS-CoV-2 WA1 and B.1.617.2 (Delta) variants. Notably, SHIELD is made with food-grade materials and does not affect normal respiratory functions. This approach could offer additional protection to the population against SARS-CoV-2 and other respiratory pathogens.}, journal={Nature Materials}, publisher={Springer Science and Business Media LLC}, author={Mei, Xuan and Li, Junlang and Wang, Zhenzhen and Zhu, Dashuai and Huang, Ke and Hu, Shiqi and Popowski, Kristen D. and Cheng, Ke}, year={2023}, month={Feb} }
 @article{wang_hu_zhu_li_cheng_liu_2023, title={Comparison of extruded cell nanovesicles and exosomes in their molecular cargos and regenerative potentials}, volume={16}, ISSN={["1998-0000"]}, DOI={10.1007/s12274-023-5374-3}, abstractNote={Extracellular vesicles (EVs) generated from mesenchymal stem cells (MSCs) play an essential role in modulating cell—cell communication and tissue regeneration. The clinical translation of EVs is constrained by the poor yield of EVs. Extrusion has recently become an effective technique for producing a large scale of nanovesicles (NVs). In this study, we systematically compared MSC NVs (from extrusion) and EVs (from natural secretion). Proteomics and RNA sequencing data revealed that NVs resemble MSCs more closely than EVs. Additionally, microRNAs in NVs are related to cardiac repair, fibrosis repression, and angiogenesis. Lastly, intravenous delivery of MSC NVs improved heart repair and cardiac function in a mouse model of myocardial infarction.}, number={5}, journal={NANO RESEARCH}, author={Wang, Xianyun and Hu, Shiqi and Zhu, Dashuai and Li, Junlang and Cheng, Ke and Liu, Gang}, year={2023}, month={May}, pages={7248–7259} }
 @article{zhu_liu_huang_li_mei_li_cheng_2023, title={Intrapericardial long non-coding RNA–<i>Tcf21</i> antisense RNA inducing demethylation administration promotes cardiac repair}, volume={44}, ISSN={0195-668X 1522-9645}, url={http://dx.doi.org/10.1093/eurheartj/ehad114}, DOI={10.1093/eurheartj/ehad114}, abstractNote={Abstract Aims Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell–derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. The aim of this study is to investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis. Methods and results Extracellular vesicles were intrapericardially injected for mice myocardial infarction treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle–based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction treatment. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA–Tcf21 antisense RNA inducing demethylation (TARID) that enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA–TARID-laden lipid nanoparticles up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction. Conclusion This study identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA–TARID-laden lipid nanoparticles could be a promising way to treat myocardial fibrosis. This study established novel mechanisms underlying EV therapy for improving adverse remodelling and proposed a lncRNA therapy for cardiac fibrosis.}, number={19}, journal={European Heart Journal}, publisher={Oxford University Press (OUP)}, author={Zhu, Dashuai and Liu, Shuo and Huang, Ke and Li, Junlang and Mei, Xuan and Li, Zhenhua and Cheng, Ke}, year={2023}, month={Mar}, pages={1748–1760} }
 @article{luo_li_bao_zhu_chen_li_xiao_wang_zhang_liu_et al._2023, title={Pericardial Delivery of SDF-1 α Puerarin Hydrogel Promotes Heart Repair and Electrical Coupling}, volume={9}, ISSN={["1521-4095"]}, DOI={10.1002/adma.202302686}, abstractNote={Abstract The stromal‐derived factor 1α/chemokine receptor 4 (SDF‐1 α /CXCR4) axis contributes to myocardial protection after myocardial infarction (MI) by recruiting endogenous stem cells into the ischemic tissue. However, excessive inflammatory macrophages are also recruited simultaneously, aggravating myocardial damage. More seriously, the increased inflammation contributes to abnormal cardiomyocyte electrical coupling, leading to inhomogeneities in ventricular conduction and retarded conduction velocity. It is highly desirable to selectively recruit the stem cells but block the inflammation. In this work, SDF‐1 α ‐encapsulated Puerarin (PUE) hydrogel (SDF‐1 α @PUE) is capable of enhancing endogenous stem cell homing and simultaneously polarizing the recruited monocyte/macrophages into a repairing phenotype. Flow cytometry analysis of the treated heart tissue shows that endogenous bone marrow mesenchymal stem cells, hemopoietic stem cells, and immune cells are recruited while SDF‐1 α @PUE efficiently polarizes the recruited monocytes/macrophages into the M2 type. These macrophages influence the preservation of connexin 43 (Cx43) expression which modulates intercellular coupling and improves electrical conduction. Furthermore, by taking advantage of the improved “soil”, the recruited stem cells mediate an improved cardiac function by preventing deterioration, promoting neovascular architecture, and reducing infarct size. These findings demonstrate a promising therapeutic platform for MI that not only facilitates heart regeneration but also reduces the risk of cardiac arrhythmias.}, journal={ADVANCED MATERIALS}, author={Luo, Li and Li, Yuetong and Bao, Ziwei and Zhu, Dashuai and Chen, Guoqin and Li, Weirun and Xiao, Yingxian and Wang, Zhenzhen and Zhang, Yixin and Liu, Huifang and et al.}, year={2023}, month={Sep} }
 @article{zhang_zhu_wei_wu_cui_liuqin_fan_yang_wang_xu_et al._2022, title={Corrigendum to ‘A collagen hydrogel loaded with HDAC7-derived peptide promotes the regeneration of infarcted myocardium with functional improvement in a rodent model’ [Acta Biomaterialia 2019, 86, 223-234] (Acta Biomaterialia (2019) 86 (223–234), (S174270611930042X), (10.1016/j.actbio.2019.01.022))}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85127693999&partnerID=MN8TOARS}, DOI={10.1016/j.actbio.2022.03.049}, journal={Acta Biomaterialia}, author={Zhang, Y. and Zhu, D. and Wei, Y. and Wu, Y. and Cui, W. and Liuqin, L. and Fan, G. and Yang, Q. and Wang, Z. and Xu, Z. and et al.}, year={2022} }
 @article{fan_li_shen_wang_liu_zhu_wang_li_popowski_ou_et al._2022, title={Decoy Exosomes Offer Protection Against Chemotherapy-Induced Toxicity}, volume={9}, ISSN={["2198-3844"]}, DOI={10.1002/advs.202203505}, abstractNote={Cancer patients often face severe organ toxicity caused by chemotherapy. Among these, chemotherapy-induced hepatotoxicity and cardiotoxicity are the main causes of death of cancer patients. Chemotherapy-induced cardiotoxicity even creates a new discipline termed “cardio-oncology”. Therefore, relieving toxicities induced by chemotherapy has become a key issue for improving the survival and quality of life in cancer patients. In this work, mesenchymal stem cell exosomes with the “G-C” abundant tetrahedral DNA nanostructure (TDN) are modified to form a decoy exosome (Exo-TDN). Exo-TDN reduces DOX-induced hepatotoxicity as the “G-C” base pairs scavenge DOX. Furthermore, Exo-TDN with cardiomyopathic peptide (Exo-TDN-PCM) is engineered for specific targeting to cardiomyocytes. Injection of Exo-TDN-PCM significantly reduces DOX-induced cardiotoxicity. Interestingly, Exo-TDN-PCM can also promote macrophage polarization into the M2 type for tissue repair. In addition, those decoy exosomes do not affect the anticancer effects of DOX. This decoy exosome strategy serves as a promising therapy to reduce chemo-induced toxicity.}, journal={ADVANCED SCIENCE}, author={Fan, Miao and Li, Hang and Shen, Deliang and Wang, Zhaoshuo and Liu, Huifang and Zhu, Dashuai and Wang, Zhenzhen and Li, Lanya and Popowski, Kristen D. and Ou, Caiwen and et al.}, year={2022}, month={Sep} }
 @article{hu_zhu_li_cheng_2022, title={Detachable Microneedle Patches Deliver Mesenchymal Stromal Cell Factor-Loaded Nanoparticles for Cardiac Repair}, volume={9}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.2c03060}, abstractNote={Intramyocardial injection is a direct and efficient approach to deliver therapeutics to the heart. However, the injected volume must be very limited, and there is injury to the injection site and leakage issues during heart beating. Herein, we developed a detachable therapeutic microneedle (MN) patch, which is comprised of mesenchymal stromal cell-secreted factors (MSCF)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) in MN tips made of elastin-like polypeptide gel, with a resolvable non-cross-linked hyaluronic acid (HA) gel as the MN base. The tips can be firmly inserted into the infarcted myocardium after base removal, and no suture is needed. In isolated neonatal rat cardiac cells, we found that the cellular uptake of MSCF-NP in the cardiomyocytes was higher than in cardiac fibroblasts. MSCF-NP promoted the proliferation of injured cardiomyocytes. In a rat model of myocardial infarction, MN-MSCF-NP treatment reduced cardiomyocyte apoptosis, restored myocardium volume, and reduced fibrosis during the cardiac remodeling process. Our work demonstrated the therapeutic potential of MN to deliver MSCF directly into the myocardium and provides a promising treatment approach for cardiac diseases.}, journal={ACS NANO}, author={Hu, Shiqi and Zhu, Dashuai and Li, Zhenhua and Cheng, Ke}, year={2022}, month={Sep} }
 @article{wang_popowski_zhu_abad_wang_liu_lutz_de naeyer_demarco_denny_et al._2022, title={Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine}, volume={7}, ISSN={["2157-846X"]}, url={https://doi.org/10.1038/s41551-022-00902-5}, DOI={10.1038/s41551-022-00902-5}, abstractNote={The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals’ lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates. An inhalable virus-like-particle consisting of exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain is stable at room temperature and elicits systemic and mucosal immune responses in small animals.}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Wang, Zhenzhen and Popowski, Kristen D. and Zhu, Dashuai and Abad, Blanca Lopez de Juan and Wang, Xianyun and Liu, Mengrui and Lutz, Halle and De Naeyer, Nicole and DeMarco, C. Todd and Denny, Thomas N. and et al.}, year={2022}, month={Jul} }
 @article{popowski_moatti_scull_silkstone_lutz_lópez de juan abad_george_belcher_zhu_mei_et al._2022, title={Inhalable dry powder mRNA vaccines based on extracellular vesicles}, volume={5}, ISSN={2590-2385}, url={http://dx.doi.org/10.1016/j.matt.2022.06.012}, DOI={10.1016/j.matt.2022.06.012}, abstractNote={•Lung extracellular vesicles (Lung-Exos) can package mRNA and protein drugs•Lung-Exos are deliverable through nebulization and dry powder inhalation•Dry powder Lung-Exos are room-temperature stable up to 28 days•Drug-loaded Lung-Exos can serve as an inhalable vaccine to illicit immune responses Research in extracellular vesicles (EVs) is important to the field of translational medicine to develop therapeutics that are limited by poor cellular targeting and efficacy. The biological composition of EVs can be exploited as drug-delivery vehicles that may be engineered for cellular targeting or eliciting specific immune responses through their functions in membrane trafficking and cellular signaling. With the molecular composition of EVs varying depending on their parent-cell origin, the derivation of EVs can further refine nanomedicine by utilizing nanoparticles that are recognized by specific cellular microenvironments. EVs are found in almost all biological fluids, opening the application of EVs as tailored drug-delivery vesicles to a wide range of diseases. Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes. Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes. IntroductionRespiratory diseases are among the leading causes of morbidity and mortality worldwide,1Wisnivesky J. De-Torres J.P. The global burden of pulmonary diseases: most prevalent problems and opportunities for improvement.Ann. Global Health. 2019; 85https://doi.org/10.5334/aogh.2411Crossref Scopus (17) Google Scholar with coronavirus disease 2019 (COVID-19)2Wang C. Horby P.W. Hayden F.G. Gao G.F. A novel coronavirus outbreak of global health concern.Lancet. 2020; 395: 470-473https://doi.org/10.1016/S0140-6736(20)30185-9Abstract Full Text Full Text PDF PubMed Scopus (3967) Google Scholar remaining prevalent in the ongoing pandemic. A wide range of therapeutics have been developed and repurposed to treat respiratory diseases, including small-molecule drugs,3Li D. 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Colloidal systems for drug delivery: from design to therapy.Trends Biotechnol. 2012; 30: 485-496https://doi.org/10.1016/j.tibtech.2012.04.008Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar A possible solution is colloidal drug-delivery systems, which help overcome poor drug solubility and hydrophobicity by providing protection through nanoparticle encapsulation.21Sharma J. Kalra S. Sharma A. Rani S. Colloidal drug carriers.Internet J. Fam. Pract. 2009; 9Google Scholar Plus, nanoparticles retained in the lung prolong drug release in the highly vascularized pulmonary and bronchial circulations.22Paranjpe M. Müller-Goymann C. Nanoparticle-mediated pulmonary drug delivery: a review.Int. J. Mol. Sci. 2014; 15: 5852-5873https://doi.org/10.3390/ijms15045852Crossref PubMed Scopus (271) Google Scholar Lipid nanoparticles (LNPs) have been successful as drug-delivery vesicles for vaccines, most notably in the liposome-encapsulated COVID-19 mRNA IM vaccines.23Nanomedicine and the COVID-19 vaccines.Nat. Nanotechnol. 2020; 15: 963https://doi.org/10.1038/s41565-020-00820-0Crossref PubMed Scopus (76) Google Scholar However, major limitations such as deep-freezing storage and healthcare professional administration have led to the expansion of the LNP platform to alternative delivery routes such as self-administered inhalation. In addition, the lung has sophisticated pulmonary defense mechanisms and surfactants that protect it against inhaled particulates and microbes.22Paranjpe M. Müller-Goymann C. Nanoparticle-mediated pulmonary drug delivery: a review.Int. J. Mol. Sci. 2014; 15: 5852-5873https://doi.org/10.3390/ijms15045852Crossref PubMed Scopus (271) Google Scholar,24Radiom M. Sarkis M. Brookes O. Oikonomou E.K. Baeza-Squiban A. Berret J.-F. Pulmonary surfactant inhibition of nanoparticle uptake by alveolar epithelial cells.Sci. Rep. 2020; 10: 19436https://doi.org/10.1038/s41598-020-76332-7Crossref PubMed Scopus (10) Google Scholar Therefore, the formulation of nanoparticle drug-delivery systems must be optimized to overcome these inherent obstacles.Exosomes, biologically derived nanoparticles, may be naturally equipped to withstand pulmonary conditions. They are nanosized extracellular vesicles secreted by numerous cell types and found in almost all biological fluids.25Théry C. Zitvogel L. Amigorena S. Exosomes: composition, biogenesis and function.Nat. Rev. Immunol. 2002; 2: 569-579https://doi.org/10.1038/nri855Crossref PubMed Scopus (3631) Google Scholar Initially regarded as cellular debris, exosomes are now understood to have potent roles in autocrine and paracrine signaling.26Maas S.L.N. Breakefield X.O. Weaver A.M. Extracellular vesicles: unique intercellular delivery vehicles.Trends Cell Biol. 2017; 27: 172-188https://doi.org/10.1016/j.tcb.2016.11.003Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar, 27Sung B.H. von Lersner A. Guerrero J. Krystofiak E.S. Inman D. Pelletier R. Zijlstra A. Ponik S.M. Weaver A.M. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells.Nat. Commun. 2020; 11: 2092https://doi.org/10.1038/s41467-020-15747-2Crossref PubMed Scopus (71) Google Scholar, 28van Niel G. D’Angelo G. Raposo G. Shedding light on the cell biology of extracellular vesicles.Nat. Rev. Mol. Cell Biol. 2018; 19: 213-228https://doi.org/10.1038/nrm.2017.125Crossref PubMed Scopus (3018) Google Scholar Originating from the endosomal system and shedding from the plasma membrane, exosomes contain various cocktails of RNA, protein, and lipid cargo with unique parent-cell signatures.29Kao C.-Y. Papoutsakis E.T. Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications.Curr. Opin. Biotechnol. 2019; 60: 89-98https://doi.org/10.1016/J.COPBIO.2019.01.005Crossref PubMed Scopus (0) Google Scholar,30Popowski K. Lutz H. Hu S. George A. Dinh P.-U. Cheng K. Exosome therapeutics for lung regenerative medicine.J. Extracell. Vesicles. 2020; 9: 1785161https://doi.org/10.1080/20013078.2020.1785161Crossref PubMed Scopus (36) Google Scholar Lung-derived exosomes can be utilized as sophisticated drug-delivery systems that offer cargo components and membrane features tailored to the lung microenvironment.20Beija M. Salvayre R. Lauth-de Viguerie N. Marty J.-D. Colloidal systems for drug delivery: from design to therapy.Trends Biotechnol. 2012; 30: 485-496https://doi.org/10.1016/j.tibtech.2012.04.008Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,31Popowski K.D. Dinh P.-U.C. George A. Lutz H. Cheng K. Exosome therapeutics for COVID-19 and respiratory viruses.View. 2021; : 20200186https://doi.org/10.1002/VIW.20200186Crossref Google Scholar Our group has demonstrated the lung regenerative abilities of human lung spheroid cells (LSCs)8Cores J. Hensley M.T. Kinlaw K. Rikard S.M. Dinh P.-U. Paudel D. Tang J. Vandergriff A.C. Allen T.A. Li Y. et al.Safety and efficacy of allogeneic lung spheroid cells in a mismatched rat model of pulmonary fibrosis.Stem Cells Transl. Med. 2017; 6: 1905-1916https://doi.org/10.1002/sctm.16-0374Crossref PubMed Scopus (18) Google Scholar,9Cores J. Dinh P.U.C. Hensley T. Adler K.B. Lobo L.J. Cheng K. A pre- investigational new drug study of lung spheroid cell therapy for treating pulmonary fibrosis.Stem Cells Transl. Med. 2020; 9: 786-798https://doi.org/10.1002/sctm.19-0167Crossref PubMed Scopus (5) Google Scholar in rodent models of idiopathic pulmonary fibrosis (IPF), and their safety and efficacy are being tested in a human clinical trial (HALT-IPF, ClinicialTrials.gov: NCT04262167). LSCs and their secreted exosomes (lung-derived extracellular vesicles [Lung-Exos]) have regenerative abilities in IPF models13Dinh P.-U.C. Paudel D. Brochu H. Popowski K.D. Gracieux M.C. Cores J. Huang K. Hensley M.T. Harrell E. Vandergriff A.C. et al.Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis.Nat. Commun. 2020; 11: 1064https://doi.org/10.1038/s41467-020-14344-7Crossref PubMed Scopus (127) Google Scholar and protective abilities against COVID-19 as decoys.32Li Z. Wang Z. Dinh P.-U.C. Zhu D. Popowski K.D. Lutz H. Hu S. Lewis M.G. Cook A. Andersen H. et al.Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19.Nat. Nanotechnol. 2021; 16: 942-951https://doi.org/10.1038/s41565-021-00923-2Crossref PubMed Scopus (43) Google Scholar In both disease models, Lung-Exos maintained therapeutic efficacy through jet-nebulization administration, demonstrating the ability of Lung-Exos to function as an inhalable drug-delivery and vaccine vehicle. Additionally, exosomes can be synthetically supplemented to enhance cellular targeting and therapeutic efficacy.33Hutcheson J.D. Aikawa E. Extracellular vesicles in cardiovascular homeostasis and disease.Curr. Opin. Cardiol. 2018; 33: 290-297https://doi.org/10.1097/HCO.0000000000000510Crossref PubMed Scopus (29) Google Scholar, 34Li S.p. Lin Z.x. Jiang X. Yu X.y. Yu X. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools.Acta Pharmacol. Sin. 2018; 39: 542-551https://doi.org/10.1038/aps.2017.178Crossref PubMed Scopus (170) Google Scholar, 35Lutz H. Popowski K.D. Dinh P.-U.C. Cheng K. Advanced nanobiomedical approaches to combat coronavirus disease of 2019.Adv. Nanobiomed Res. 2021; : 2000063https://doi.org/10.1002/anbr.202000063Crossref PubMed Google Scholar For example, anti-inflammatory peptides36Kim G.Y. Lee Y. Ha J. Han S. Lee M. Engineering exosomes for pulmonary delivery of peptides and drugs to inflammatory lung cells by inhalation.J. Contr. Release. 2021; 330: 684-695https://doi.org/10.1016/j.jconrel.2020.12.053Crossref PubMed Scopus (21) Google Scholar can be linked onto the exosomal membrane, engineering an immune cell targeting nanomedicine. The combination of vesicle derivation and supplementation allows for a customizable nanoparticle delivery platform that can be utilized across many lung diseases.Although exosomes as inhaled therapeutics and RNA delivery vehicles have been demonstrated,13Dinh P.-U.C. Paudel D. Brochu H. Popowski K.D. Gracieux M.C. Cores J. Huang K. Hensley M.T. Harrell E. Vandergriff A.C. et al.Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis.Nat. Commun. 2020; 11: 1064https://doi.org/10.1038/s41467-020-14344-7Crossref PubMed Scopus (127) Google Scholar,37Zhang D. Lee H. Wang X. Rai A. Groot M. Jin Y. Exosome-Mediated small RNA delivery: a novel therapeutic approach for inflammatory lung responses.Mol. Ther. 2018; 26: 2119-2130https://doi.org/10.1016/j.ymthe.2018.06.007Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar the distribution and retention of exosome particles in the lung have yet to be determined. Drug effectiveness depends on proper deposition of particles within the respirable fraction, requiring optimized nanoparticle formulation. In this study, we sought to elucidate the biodistribution of lung-derived exosomes upon nebulization, baselined to liposomes (Lipos) as a commercial standard. Furthermore, to provide a room-temperature-stable product, we formulated exosomes as a lyophilized dry powder to investigate their stability and inhaled biodistribution in the lung of both the mouse and African green monkey (AGM). The parent-cell signature of Lung-Exos may suggest that they are naturally optimized for the distribution and retention within the lung, which may allow them to bypass pulmonary clearance more efficiently than Lipos or exosomes derived from other cell types. Through this enhanced pulmonary bioavailability, we hypothesize that lung-derived exosomes elicit greater therapeutic responses for pulmonary diseases and serve as a customizable drug-delivery vehicle for room-temperature-stable inhaled mRNA therapeutics.ResultsExosome distribution in the bronchioles and parenchyma are superior to that of synthetic nanoparticlesRed fluorescent protein (RFP)-labeled lung-derived exosomes (RFP-Exos) and Lipos (RFP-Lipos) were fabricated to generate trackable nanoparticles for biodistribution analysis in the murine lung after inhalation treatment through three-dimensional (3D) imaging (Figure 1A ). The nanoparticles were characterized by transmission electron microscopy (TEM), confirming that the isolation of exosomes and Lipos did not disrupt vesicular membrane integrity (Figure 1B). RFP loading was verified by immunoblotting (Figure 1C). When co-cultured with lung parenchymal cells, RFP-Exo had a 6.7-fold increase in cellular uptake and RFP protein expression compared with cells cultured with RFP-Lipo (Figures 1D and 1E). Next, the biodistribution of nanoparticles in vivo were evaluated through light-sheet fluorescence microscopy (LSFM) (Figure 1F). Healthy mice received a single dose of RFP-Exos or RFP-Lipos via nebulization and were sacrificed after 24 h. LSFM imaging confirmed nanoparticle delivery to the conducting airways and the deep lung, with an accumulation of RFP-Exos in the upper pulmonary regions (Videos S1 and S2). Quantification of nanoparticle delivery to the whole lung demonstrated a 3.7-fold improvement in RFP-Exo retention and uptake compared with RFP-Lipo (Figure 1G). Segmentation of the lung into bronchial and parenchymal regions revealed 2.9- and 3.8-fold improvements in RFP-Exo retention and uptake, respectively, compared with RFP-Lipo (Figure 1H). Flow cytometry analysis in lung parenchymal cells (Figure 1I) and in the murine lung following nebulization (Figure 1J) confirmed greater cellular uptake of RFP-Exos than RFP-Lipos. The drug-loading capabilities of lung-derived exosomes (Lung-Exos and Lipos were expanded by loading GFP-encoding mRNA to evaluate nanoparticle mRNA uptake. Lung parenchymal cells that received GFP-Exos demonstrated more rapid internalization of exosomal mRNA than liposomal mRNA (Figure S1). These data confirm that our nanoparticle labeling system maintains nanoparticle integrity while delivering functional and translatable cargo after jet nebulization. In vitro and in vivo analyses suggest superior retention and cellular uptake of exosomes over Lipos in the lung. The native lung signature of lung-derived exosomes may enhance pulmonary bioavailability, resulting in an optimized nanoparticle vesicle for drug delivery for respiratory diseases.eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyZDE5ZTI0ODk4NDRkYTFhYjJlNGUzMWEwMGE4OTEyYyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjY5OTY2NjUwfQ.ZP_2__aVFlfG_3XKl06osGFI0GeEXb27ElTxZ-KGGM8IcSO676pqZKF6h65jz0cnnYuojIwvoPOnatMAd9qqR65EtMzNhGLYU-TdT2hEgjFIUL9AatnXvIyrTXEJt4Orap9iWn8eBBxr63jGbLdLvzqnA2A05saBmcwbPhbN3bVzqdWYJQCLOpzv6z8Yi-0i3xtJfwEmLHgdsvSLgQt8vnGKzY4IUA9jBXCdfho1Cp5PVg3eCXd0p9bQo-Df_q9s-Ghg1957V4C1OlRDoKdNdXo62FKjOcdLZPrCnVgzDNqmk_IPHTSkzr3rdFCG41UJVBXHBYkJMpXnhOvsDyhoXw Download .mp4 (30.4 MB) Help with .mp4 files Video S1. Biodistribution of nebulized RFP-Exos in mouse lungsLSFM imaging and 3D rendering and animation by Imaris confirms labeled exosome distribution throughout the lung. Tissue autofluorescence allows for morphological segmentation of bronchioles and parenchyma to quantify exosome distribution.eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJiNTYzZTFmZDNiYjJiOTQzMWQyMDAwODQzYzA2MDcxNCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjY5OTY2NjUwfQ.rrwycH66nt21uB8nXcVXQaa02xcRy_2vJlbQsIigymt2QlJ24qCloQxenvyl4rqzmA9WIpCs6ZdvZ5yRY5FWlu-j2SfO4Sl8lcL2Xz3jrbu8PU-Ge_avejxOWdeaYEEEGIbmAWmXlVHWH2p6_LlFpfPB-j4E-KTapjf5CHzT4rGRom3mXroj6OiJkAkRl3ylnmxTdNaQDUbtDr2dJvIYzLCX_8TUNx9a7L4Rz-65ZWZD_ZXLADu_bgTFdnNOGodGmEY-9NZhPBqraOljjTPxzbe4TJJOttzGsmAySGpVDMWGFGcStxkuif_tgwujLF5wcLU1o-KQtk8eosKrcuRuxA Download .mp4 (38.39 MB) Help with .mp4 files Video S2. Biodistribution of nebulized RFP-Lipos in mouse lungsLSFM imaging and 3D rendering and animation by Imaris confirms labeled liposome distribution throughout the lung. Tissue autofluorescence allows for morphological segmentation of bronchioles and parenchyma to quantify liposome distribution.Lung-derived exosomes efficiently penetrate mucusDelivery of inhaled therapeutics must penetrate the lung’s protective mucus lining to provide pulmonary bioavailability. Lung-Exos were compared against human embryonic kidney (HEK)-derived exosomes (HEK-Exos) and Lipos to determine if nanoparticle derivation affected mucus penetrance. To test this, we used a model of the human airway at the air-liquid interface (Figure S2A), with human mucus-secreting bronchial epithelial cells lining the transwell membrane and human lung parenchymal cells lining the well (Figure S2B). Immunostaining confirmed the mucus lining in the transwell membrane and delivery of DiD-labeled nanoparticles (Figure S2C). Quantification of nanoparticle penetrance into the wells revealed the greatest uptake of Lung-Exos (Figure S2D), with the highest percentage of cellular uptake by lung parenchymal cells (Figure S2E) by 24 h. Likewise, Lung-Exos had the least entrapment by the mucus-lined membrane (Figure S2F) and the lowest percentage of cellular uptake by bronchial epithelial cells (Figure S2G). These data confirm mucus penetrance of the nanoparticles and suggest that Lung-Exos can most efficiently evade mucoadhesion, overcoming the lung’s natural defense mechanism and allowing for greater parenchymal bioavailability.Lung-derived exosomes are room-temperature stable and distributable in dry powder formulation in the murine lungRoom-temperature formulation of therapeutics circumvents major limitations in traditional IM vaccine delivery: deep-freezing storage, healthcare professional administration, and reduced patient compliance. Therefore, we reformulated our liquid nanoparticle suspensions into dry, lyophilized powder for dry powder inhalation (DPI) administration. We verified the efficacy and stability of room-temperature lyophilized Lung-Exos up to 28 days in the murine lung (Figure 2A ). To verify dry powder nanoparticle stability and shelf life, lyophilized nanoparticle cargo leakage was tested by an enzyme-linked immunosorbent assay (ELISA), where nanoparticles had less than 2.4% of total pg/mL cargo leakage at day 28 of room-temperature storage (Figures 2B and S3). Next, the morphology of nanoparticles was evaluated across their fresh and lyophilized formulations, as well as lyophilized powder reconstituted in water (reconstituted), to mimic rehydration of dry powder by saliva and mucus. TEM (Figures 2E and S4) and atomic force microscopy (AFM) verified that reformulation and rehydration did not affect nanoparticle membrane integrity (Figures 2C and S5) but did affect size distributions through clumping (Figure S6–S8). Lyophilization increased nanoparticle height and diameter (Figure 2D) but remained as small respiratory droplets upon reconstitution. Across all formulations, the nanoparticle diameters are approximately 10-fold larger, which may be explained by tip dilation38Wong C. West P.E. Olson K.S. Mecartney M.L. Starostina N. Tip dilation and AFM capabilities in the characterization of nanoparticles.JOM. 2007; 59: 12-16https://doi.org/10.1007/s11837-007-0003-xCrossref Scopus (40) Google Scholar that reports larger lateral dimensions than 2D analysis such as through TEM.39Eaton P. Quaresma P. Soares C. Neves C. de Almeida M.P. Pereira E. West P. A direct comparison of experimental methods to measure dimensions of synthetic nanoparticles.Ultramicroscopy. 2017; 182: 179-190https://doi.org/10.1016/j.ultramic.2017.07.001Crossref PubMed Scopus (164) Google Scholar Cross-section measurement curves demonstrate a restoration of membrane “smoothness” in reconstituted nanoparticles, mimicking fresh formulation (Figure S9). Next, we delivered the lyophilized Lung-Exos via DPI, where ex vivo images (Figure 2F) of mouse lungs who received fresh (fresh lyophilized) and 28-day-old (28-day lyophilized) dry powder Lung-Exos had no significant difference in exosomal mRNA and protein distribution (Figure 2G). mRNA activity showed greater variability at it 28-day-old state, but protein activity remained more stable.Figure 2Stability and distribution of lung-derived exosomes in dry powder formulation in the murine lungShow full caption(A) Schematic of mRNA and protein-loaded lung-derived exosome lyophilization, encapsulation, rodent DPI administration, and ex vivo histology. Created with BioRender.com.(B) Heatmaps of RFP leakage from Lung-Exos, HEK-Exos, and Lipos detected by ELISA; n = 2 per group.(C) Representative AFM height (I), amplitude (II), and phase (III) images of Lung-Exos; scale bar: 50 nm.(D) Quantification of the height and diameter of Lung-Exos, HEK-Exos, and Lipos from AFM images; n = 9 per group; data are represented as mean ± standard deviation.(E) TEM images of Lung-Exos at frozen (Frozen) or room (Lyophilized) temperatures; scale bar: 50 nm.(F) Ex vivo images of mouse lungs that received fresh lyophilized (0 days) and 28-day-old lyophilized Lung-Exos via dry powder inhalation after 24 h.(G) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after fresh (Fresh-Lyos) and 28-day-old (28-Day Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.(H) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after nebulization and fresh (Fresh-Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.(I) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after nebulization and 28-day-old (28-Day Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.View Large}, number={9}, journal={Matter}, publisher={Elsevier BV}, author={Popowski, Kristen D. and Moatti, Adele and Scull, Grant and Silkstone, Dylan and Lutz, Halle and López de Juan Abad, Blanca and George, Arianna and Belcher, Elizabeth and Zhu, Dashuai and Mei, Xuan and et al.}, year={2022}, month={Sep}, pages={2960–2974} }
 @article{zhu_liu_huang_wang_hu_li_li_cheng_2022, title={Intrapericardial Exosome Therapy Dampens Cardiac Injury via Activating Foxo3}, volume={131}, ISSN={["1524-4571"]}, url={https://doi.org/10.1161/CIRCRESAHA.122.321384}, DOI={10.1161/CIRCRESAHA.122.321384}, abstractNote={Mesenchymal stem cell (MSC)-derived exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. The Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes.Myocardial infarction (MI) models with and without pericardiectomy (corresponding to Tomy MI and NonTomy MI) were established to study the functions of pericardial drainage pathway in immune activation of cardiac-draining mediastinal lymph node (MLN). Using the NonTomy MI model, MSC exosomes or vehicle PBS was intrapericardially injected for MI treatment. Via cell sorting and RNA-seq (RNA-sequencing) analysis, the differentially expressed genes were acquired for integrated pathway analysis to identify responsible mechanisms. Further, through functional knockdown/inhibition studies, application of cytokines and neutralizing antibodies, western blot, flow cytometry, and cytokine array, the molecular mechanisms were studied. In addition, the therapeutic efficacy of intrapericardially injected exosomes for MI treatment was evaluated through functional and histological analyses.We show that the pericardial draining pathway promoted immune activation in the MLN following MI. Intrapericardially injected exosomes accumulated in the MLN and induced regulatory T cell differentiation to promote cardiac repair. Mechanistically, uptake of exosomes by major histocompatibility complex (MHC)-II+ antigen-presenting cells (APCs) induced Foxo3 activation via the protein phosphatase (PP)-2A/p-Akt/forkhead box O3 (Foxo3) pathway. Foxo3 dominated APC cytokines (IL-10, IL-33, and IL-34) expression and built up a regulatory T cell (Treg)-inducing niche in the MLN. The differentiation of Tregs as well as their cardiac deployment were elevated, which contributed to cardiac inflammation resolution and cardiac repair.This study reveals a novel mechanism underlying the immunomodulation effects of MSC exosomes and provides a promising candidate (PP2A/p-Akt/Foxo3 signaling pathway) with a favorable delivery route (intrapericardial injection) for cardiac repair.}, number={10}, journal={CIRCULATION RESEARCH}, author={Zhu, Dashuai and Liu, Shuo and Huang, Ke and Wang, Zhenzhen and Hu, Shiqi and Li, Junlang and Li, Zhenhua and Cheng, Ke}, year={2022}, month={Oct}, pages={E135–E150} }
 @article{li_lv_zhu_mei_huang_wang_li_zhang_hu_popowski_et al._2022, title={Intrapericardial hydrogel injection generates high cell retention and augments therapeutic effects of mesenchymal stem cells in myocardial infarction}, volume={427}, ISSN={["1873-3212"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85113941738&partnerID=MN8TOARS}, DOI={10.1016/j.cej.2021.131581}, abstractNote={Although cell therapy has shown potential efficacy in the treatment of heart diseases, one challenge is low cellular retention rate and poor engraftment. We sought to perform a head-to-head comparison on cell retention and therapeutic benefits of intramyocardial (IM) injection and intrapericardial cavity (IPC) injection of adult stem cells in hydrogel. Mouse green fluorescent protein (GFP)-labeled mesenchymal stem cells (MSCs) were combined in extracellular matrix (ECM) hydrogel and injected into the pericardial cavity or the myocardium of the heart of C57BL/6 mice that had been subjected to a myocardial infarction. The IPC injection, as an alternative cell delivery route, led to better cardiac function in our mouse model with myocardial infarction, which was showed by echocardiographies in the short term (2 weeks) and the long term (6 weeks). This result was attributed to 10-fold higher engraftment of MSCs injected via IPC route (42.5 ± 7.4%) than that of MSCs injected intramyocardially (4.4 ± 1.3%). Immunohistochemistry data revealed better cellular proliferation, less apoptosis, and better vascular regeneration in the myocardium after IPC delivery of MSCs. CD63-RFP exosome labeling system showed that heart cells including cardiomyocytes absorbed MSC-exosomes at higher rates when MSCs were injected via IPC route, compared to the results from IM injections, indicating more extensive paracrine activity of MSCs after IPC injections. What is more, the feasibility and safety of IPC injection were demonstrated in a porcine model with minimally invasive procedure. Intrapericardial cavity injection gave a promising solution for the low retention issue of MSCs in the infarcted heart.}, journal={CHEMICAL ENGINEERING JOURNAL}, publisher={Elsevier BV}, author={Li, Junlang and Lv, Yongbo and Zhu, Dashuai and Mei, Xuan and Huang, Ke and Wang, Xianyun and Li, Zhenhua and Zhang, Sichen and Hu, Shiqi and Popowski, Kristen D. and et al.}, year={2022}, month={Jan} }
 @article{cheng_zhu_huang_caranasos_2022, title={Minimally invasive delivery of a hydrogel-based exosome patch to prevent heart failure}, volume={169}, ISSN={["1095-8584"]}, DOI={10.1016/j.yjmcc.2022.04.020}, abstractNote={Coronary heart disease (CHD) has been the number one killer in the United States for decades and causes millions of deaths each year. Clinical treatment of heart ischemic injury relieves symptoms in the acute stage of CHD; however, patients with an infarcted heart muscle can develop heart failure (HF) due to chronic maladaptive remodeling. Regenerative therapy has been studied as a potential treatment option for myocardial infarction (MI) and HF. Cardiac patches have been designed and tested to increase therapeutic retention and integration. However, the delivery usually requires invasive surgical techniques, including open-chest surgeries and heart manipulation. Those procedures may cause chronic adhesions between the heart anterior wall and the chest wall. This study created and tested an injectable ExoGel by embedding mesenchymal stem cell (MSC) -derived exosomes into a hyaluronic acid (HA) hydrogel. ExoGel was injected into the pericardial cavity of rats with transverse aortic constriction (TAC) induced heart failure. ExoGel therapy reduced LV chamber size and preserved wall thickness. The feasibility and safety of ExoGel injection were further confirmed in a pig model.}, journal={JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY}, author={Cheng, George and Zhu, Dashuai and Huang, Ke and Caranasos, Thomas G.}, year={2022}, month={Aug}, pages={113–121} }
 @article{zhang_zhang_zhu_li_wang_li_mei_xu_cheng_zhong_2022, title={Nanoparticles functionalized with stem cell secretome and CXCR4-overexpressing endothelial membrane for targeted osteoporosis therapy}, volume={20}, ISSN={["1477-3155"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85122993345&partnerID=MN8TOARS}, DOI={10.1186/s12951-021-01231-6}, abstractNote={Abstract Background Osteoporosis is a chronic condition affecting patients’ morbidity and mortality and represents a big socioeconomic burden. Because stem cells can proliferate and differentiate into bone-forming cells, stem cell therapy for osteoporosis has been widely studied. However, cells as a live drug face multiple challenges because of their instability during preservation and transportation. In addition, cell therapy has potential adverse effects such as embolism, tumorigenicity, and immunogenicity. Results Herein, we sought to use cell-mimicking and targeted therapeutic nanoparticles to replace stem cells. We fabricated nanoparticles (NPs) using polylactic-co-glycolic acid (PLGA) loaded with the secretome (Sec) from mesenchymal stem cells (MSCs) to form MSC-Sec NPs. Furthermore, we cloaked the nanoparticles with the membranes from C–X–C chemokine receptor type 4 (CXCR4)-expressing human microvascular endothelial cells (HMECs) to generate MSC-Sec/CXCR4 NP. CXCR4 can target the nanoparticles to the bone microenvironment under osteoporosis based on the CXCR4/SDF-1 axis. Conclusions In a rat model of osteoporosis, MSC-Sec/CXCR4 NP were found to accumulate in bone, and such treatment inhibited osteoclast differentiation while promoting osteogenic proliferation. In addition, our results showed that MSC-Sec/CXCR4 NPs reduce OVX-induced bone mass attenuation in OVX rats. Graphical Abstract}, number={1}, journal={JOURNAL OF NANOBIOTECHNOLOGY}, author={Zhang, Chi and Zhang, Wei and Zhu, Dashuai and Li, Zhenhua and Wang, Zhenzhen and Li, Junlang and Mei, Xuan and Xu, Wei and Cheng, Ke and Zhong, Biao}, year={2022}, month={Jan} }
 @article{yao_huang_zhu_chen_jiang_zhang_mi_xuan_hu_li_et al._2021, title={A Minimally Invasive Exosome Spray Repairs Heart after Myocardial Infarction}, volume={15}, ISSN={["1936-086X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85110404046&partnerID=MN8TOARS}, DOI={10.1021/acsnano.1c00628}, abstractNote={Myocardial infarction (MI) remains the most common cause of death worldwide. Many MI survivors will suffer from recurrent heart failure (HF), which has been recognized as a determinant of adverse prognosis. Despite the success of improved early survival after MI by primary percutaneous coronary intervention, HF after MI is becoming the major driver of late morbidity, mortality, and healthcare costs. The development of regenerative medicine has brought hope to MI treatment in the past decade. Mesenchymal stem cell (MSC)-derived exosomes have been established as an essential part of stem cell paracrine factors for heart regeneration. However, its regenerative power is hampered by low delivery efficiency to the heart. We designed, fabricated, and tested a minimally invasive exosome spray (EXOS) based on MSC exosomes and biomaterials. In a mouse model of acute myocardial infarction, EXOS improved cardiac function and reduced fibrosis, and promoted endogenous angiomyogenesis in the post-injury heart. We further tested the feasibility and safety of EXOS in a pig model. Our results indicate that EXOS is a promising strategy to deliver therapeutic exosomes for heart repair.}, number={7}, journal={ACS NANO}, publisher={American Chemical Society (ACS)}, author={Yao, Jialu and Huang, Ke and Zhu, Dashuai and Chen, Tan and Jiang, Yufeng and Zhang, Junyi and Mi, Lijie and Xuan, He and Hu, Shiqi and Li, Junlang and et al.}, year={2021}, month={Jul}, pages={11099–11111} }
 @article{mei_zhu_li_huang_hu_li_abad_cheng_2021, title={A fluid-powered refillable origami heart pouch for minimally invasive delivery of cell therapies in rats and pigs}, volume={2}, ISSN={["2666-6340"]}, url={https://doi.org/10.1016/j.medj.2021.10.001}, DOI={10.1016/j.medj.2021.10.001}, abstractNote={BackgroundCardiac repair after heart injury remains a big challenge, and current drug delivery to the heart is suboptimal. Repeated dosing of therapeutics is difficult due to the invasive nature of such procedures.MethodsWe developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The pore size of the membrane is around 0.4 μm, which allows for the penetration of growth factors and exosomes.FindingsWe tested the pouch’s ability to deliver mesenchymal stem cells (MSCs) in a rodent model of acute myocardial infarction and demonstrated the feasibility of minimally invasive delivery in a swine model. The pouch’s semi-permeable membrane successfully protected delivered cells from their surroundings, maintaining their viability while releasing growth factors and exosomes to the infarcted site for cardiac repair.ConclusionsIn summary, we developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The origami structure allowed minimally invasive delivery of the pouch to the heart and can be refilled with the therapeutic of choice.FundingThis work was supported by grants from the NIH ( HL123920 , HL137093 , HL144002 , HL146153 , HL147357 , and HL149940 to K.C.) and the American Heart Association ( 18TPA34230092 and 19EIA34660286 to K.C.).}, number={11}, journal={MED}, publisher={Elsevier BV}, author={Mei, Xuan and Zhu, Dashuai and Li, Junlang and Huang, Ke and Hu, Shiqi and Li, Zhenhua and Abad, Blanca Lopez de Juan and Cheng, Ke}, year={2021}, month={Nov}, pages={1253-+} }
 @article{zhang_zhu_li_huang_hu_lutz_xie_mei_li_neal-perry_et al._2021, title={A stem cell-derived ovarian regenerative patch restores ovarian function and rescues fertility in rats with primary ovarian insufficiency}, volume={11}, ISSN={["1838-7640"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85114771196&partnerID=MN8TOARS}, DOI={10.7150/thno.61690}, abstractNote={Rationale: Primary ovarian insufficiency (POI) normally occurs before age 40 and is associated with infertility. Hormone replacement therapy is often prescribed to treat vasomotor symptom, but it cannot restore ovarian function or fertility. Stem cell therapy has been studied for the treatment of POI. However, the application of live stem cells has suffered from drawbacks, such as low cell retention/engraftment rate, risks for tumorigenicity and immunogenicity, and lack of off-the-shelf feasibility. Methods: We developed a therapeutic ovarian regenerative patch (ORP) that composed of clinically relevant hydrolysable scaffolds and synthetic mesenchymal stem cells (synMSCs), which are microparticles encapsulating the secretome from MSCs. The therapeutic potency of ORP was tested in rats with cisplatin induced POI injury. Results:In vitro studies revealed that ORP stimulated proliferation of ovarian somatic cells (OSCs) and inhibited apoptosis under injury stress. In a rat model of POI, implantation of ORP rescued fertility by restoring sexual hormone secretion, estrus cycle duration, and follicle development. Conclusion: ORP represents a cell-free, off-the-shelf, and clinically feasible treatment for POI.}, number={18}, journal={THERANOSTICS}, author={Zhang, Sichen and Zhu, Dashuai and Li, Zhenhua and Huang, Ke and Hu, Shiqi and Lutz, Halle and Xie, Mengjie and Mei, Xuan and Li, Junlang and Neal-Perry, Genevieve and et al.}, year={2021}, pages={8894–8908} }
 @article{xie_li_zhang_zhu_mei_wang_cheng_li_wang_cheng_2021, title={A trifunctional contraceptive gel enhances the safety and quality of sexual intercourse}, volume={6}, ISSN={["2452-199X"]}, url={https://doi.org/10.1016/j.bioactmat.2020.11.031}, DOI={10.1016/j.bioactmat.2020.11.031}, abstractNote={Current contraceptive methods come with a number of drawbacks, including low efficacy, in the case of commercial contraceptive gels, and a reduction in the quality of sexual intercourse, in the case of condoms. Adding pharmacologically-active agents to contraceptive gels holds the potential to improve sexual experience, and hardbor safety and hygiene. In this study, we fabricated a carbomer-based contraceptive gel consisting of three agents: tenofovir, gossypol acetate, and nitroglycerin (TGN), with pH adjusted to 4.5 (to be compatible with the vagina). In vitro, the gossypol component of the contraceptive gel proved to be an effective spermicide. When the concentration of gossypol acetate was 10 mg/ml, the spermicidal ability reached 100% after 30 s. In addition, tenofovir in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media. In 6 pairs of rats, the gel successfully prevented all females from conceiving after successful mating. Moreover, increased sexual frequency and enhanced erection, which were promoted by the nitroglycerin in the components, were observed in male rats that had the gel applied to their penises. This novel TGN contraceptive gel yielded a higher contraceptive success rate than that of the commercial contraceptive gel (Contragel®). In addition, it has the added benefits to prevent sexually transmitted diseases and improve male libido and erectile function during sexual intercourse. Combining three FDA-approved and marketed agents together, our trifunctional TGN gel has a great potential for further translation and commercialization.}, number={6}, journal={BIOACTIVE MATERIALS}, publisher={Elsevier BV}, author={Xie, Mengjie and Li, Junlang and Zhang, Sichen and Zhu, Dashuai and Mei, Xuan and Wang, Zhenzhen and Cheng, Xiao and Li, Zhenhua and Wang, Shaowei and Cheng, Ke}, year={2021}, month={Jun}, pages={1777–1788} }
 @misc{zhang_zhu_mei_li_li_xie_xie_wang_cheng_2021, title={Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy}, volume={6}, ISSN={["2452-199X"]}, url={https://doi.org/10.1016/j.bioactmat.2020.12.008}, DOI={10.1016/j.bioactmat.2020.12.008}, abstractNote={Primary ovarian insufficiency (POI) is an ovarian dysfunction that affects more than 1 % of women and is characterized by hormone imbalances that afflict women before the age of 40. The typical perimenopausal symptoms result from abnormal levels of sex hormones, especially estrogen. The most prevalent treatment is hormone replacement therapy (HRT), which can relieve symptoms and improve quality of life. However, HRT cannot restore ovarian functions, including secretion, ovulation, and fertility. Recently, as part of a developing field of regenerative medicine, stem cell therapy has been proposed for the treatment of POI. Thus, we recapitulate the literature focusing on the use of stem cells and biomaterials for POI treatment, and sum up the underlying mechanisms of action. A thorough understanding of the work already done can aid in the development of guidelines for future translational applications and clinical trials that aim to cure POI by using regenerative medicine and biomedical engineering strategies.}, number={7}, journal={BIOACTIVE MATERIALS}, publisher={Elsevier BV}, author={Zhang, Sichen and Zhu, Dashuai and Mei, Xuan and Li, Zhenhua and Li, Junlang and Xie, Mengjie and Xie, Halle Jiang Williams and Wang, Shaowei and Cheng, Ke}, year={2021}, month={Jul}, pages={1957–1972} }
 @misc{li_hu_zhu_huang_mei_abad_cheng_2021, title={All Roads Lead to Rome (the Heart): Cell Retention and Outcomes From Various Delivery Routes of Cell Therapy Products to the Heart}, volume={10}, ISSN={["2047-9980"]}, url={https://doi.org/10.1161/JAHA.120.020402}, DOI={10.1161/JAHA.120.020402}, abstractNote={Abstract In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell‐mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in‐depth study of primary theories of cell loss, including low efficiency in cell injection, “washout” effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state‐of‐the‐art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.}, number={8}, journal={JOURNAL OF THE AMERICAN HEART ASSOCIATION}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Li, Junlang and Hu, Shiqi and Zhu, Dashuai and Huang, Ke and Mei, Xuan and Abad, Blanca Lopez de Juan and Cheng, Ke}, year={2021}, month={Apr} }
 @article{chingale_zhu_cheng_huang_2021, title={Bioengineering Technologies for Cardiac Regenerative Medicine}, volume={9}, ISSN={2296-4185}, url={http://dx.doi.org/10.3389/fbioe.2021.681705}, DOI={10.3389/fbioe.2021.681705}, abstractNote={Cardiac regenerative medicine faces big challenges such as a lack of adult cardiac stem cells, low turnover of mature cardiomyocytes, and difficulty in therapeutic delivery to the injured heart. The interaction of bioengineering and cardiac regenerative medicine offers innovative solutions to this field. For example, cell reprogramming technology has been applied by both direct and indirect routes to generate patient-specific cardiomyocytes. Various viral and non-viral vectors have been utilized for gene editing to intervene gene expression patterns during the cardiac remodeling process. Cell-derived protein factors, exosomes, and miRNAs have been isolated and delivered through engineered particles to overcome many innate limitations of live cell therapy. Protein decoration, antibody modification, and platelet membranes have been used for targeting and precision medicine. Cardiac patches have been used for transferring therapeutics with better retention and integration. Other technologies such as 3D printing and 3D culture have been used to create replaceable cardiac tissue. In this review, we discuss recent advancements in bioengineering and biotechnologies for cardiac regenerative medicine.}, journal={Frontiers in Bioengineering and Biotechnology}, publisher={Frontiers Media SA}, author={Chingale, Mira and Zhu, Dashuai and Cheng, Ke and Huang, Ke}, year={2021}, month={Jun} }
 @article{liu_lutz_zhu_huang_li_dinh_gao_zhang_cheng_2021, title={Bispecific Antibody Inhalation Therapy for Redirecting Stem Cells from the Lungs to Repair Heart Injury}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85096756888&partnerID=MN8TOARS}, DOI={10.1002/advs.202002127}, abstractNote={Abstract Stem cell therapy is a promising strategy for cardiac repair. However, clinical efficacy is hampered by poor cell engraftment and the elusive repair mechanisms of the transplanted stem cells. The lung is a reservoir of hematopoietic stem cells (HSCs) and a major biogenesis site for platelets. A strategy is sought to redirect lung resident stem cells to the injured heart for therapeutic repair after myocardial infarction (MI). To achieve this goal, CD34‐CD42b platelet‐targeting bispecific antibodies (PT‐BsAbs) are designed to simultaneously recognize HSCs (via CD34) and platelets (via CD42b). After inhalation delivery, PT‐BsAbs reach the lungs and conjoined HSCs and platelets. Due to the innate injury‐finding ability of platelets, PT‐BsAbs guide lung HSCs to the injured heart after MI. The redirected HSCs promote endogenous repair, leading to increased cardiac function. The repair mechanism involves angiomyogenesis and inflammation modulation. In addition, the inhalation route is superior to the intravenous route to deliver PT‐BsAbs in terms of the HSCs’ homing ability and therapeutic benefits. This work demonstrates that this novel inhalable antibody therapy, which harnesses platelets derived from the lungs, contributes to potent stem cell redirection and heart repair. This strategy is safe and effective in a mouse model of MI.}, number={1}, journal={Advanced Science}, author={Liu, M. and Lutz, H. and Zhu, D. and Huang, K. and Li, Z. and Dinh, P.-U.C. and Gao, J. and Zhang, Y. and Cheng, K.}, year={2021} }
 @misc{zhu_cheng_2021, title={Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out?}, volume={10}, ISSN={["2073-4409"]}, url={https://doi.org/10.3390/cells10030641}, DOI={10.3390/cells10030641}, abstractNote={Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation.}, number={3}, journal={CELLS}, publisher={MDPI AG}, author={Zhu, Dashuai and Cheng, Ke}, year={2021}, month={Mar} }
 @article{li_wang_dinh_zhu_popowski_lutz_hu_lewis_cook_andersen_et al._2021, title={Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19}, volume={6}, url={https://doi.org/10.1038/s41565-021-00923-2}, DOI={10.1038/s41565-021-00923-2}, abstractNote={Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.}, number={8}, journal={Nature Nanotechnology}, publisher={Springer Science and Business Media LLC}, author={Li, Zhenhua and Wang, Zhenzhen and Dinh, Phuong-Uyen C. and Zhu, Dashuai and Popowski, Kristen D. and Lutz, Halle and Hu, Shiqi and Lewis, Mark G. and Cook, Anthony and Andersen, Hanne and et al.}, year={2021}, month={Aug}, pages={942–951} }
 @article{hu_li_shen_zhu_huang_su_dinh_cores_cheng_2021, title={Exosome-eluting stents for vascular healing after ischaemic injury}, volume={5}, ISSN={["2157-846X"]}, url={https://doi.org/10.1038/s41551-021-00705-0}, DOI={10.1038/s41551-021-00705-0}, abstractNote={Drug-eluting stents implanted after ischaemic injury reduce the proliferation of endothelial cells and vascular smooth muscle cells and thus neointimal hyperplasia. However, the eluted drug also slows down the re-endothelialization process, delays arterial healing and can increase the risk of late restenosis. Here we show that stents releasing exosomes derived from mesenchymal stem cells in the presence of reactive oxygen species enhance vascular healing in rats with renal ischaemia-reperfusion injury, promoting endothelial cell tube formation and proliferation, and impairing the migration of smooth muscle cells. Compared with drug-eluting stents and bare-metal stents, the exosome-coated stents accelerated re-endothelialization and decreased in-stent restenosis 28 days after implantation. We also show that exosome-eluting stents implanted in the abdominal aorta of rats with unilateral hindlimb ischaemia regulated macrophage polarization, reduced local vascular and systemic inflammation, and promoted muscle tissue repair.}, number={10}, journal={NATURE BIOMEDICAL ENGINEERING}, publisher={Springer Science and Business Media LLC}, author={Hu, Shiqi and Li, Zhenhua and Shen, Deliang and Zhu, Dashuai and Huang, Ke and Su, Teng and Dinh, Phuong-Uyen and Cores, Jhon and Cheng, Ke}, year={2021}, month={Oct}, pages={1174–1188} }
 @article{wang_hu_li_zhu_wang_cores_cheng_liu_huang_2021, title={Extruded Mesenchymal Stem Cell Nanovesicles Are Equally Potent to Natural Extracellular Vesicles in Cardiac Repair}, volume={13}, ISSN={["1944-8252"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85119954105&partnerID=MN8TOARS}, DOI={10.1021/acsami.1c08044}, abstractNote={Mesenchymal stem cells (MSCs) repair injured tissues mainly through their paracrine actions. One of the important paracrine components of MSC secretomes is the extracellular vesicle (EV). The therapeutic potential of MSC-EVs has been established in various cardiac injury preclinical models. However, the large-scale production of EVs remains a challenge. We sought to develop a scale-up friendly method to generate a large number of therapeutic nanovesicles from MSCs by extrusion. Those extruded nanovesicles (NVs) are miniature versions of MSCs in terms of surface marker expression. The yield of NVs is 20-fold more than that of EVs. In vitro, cell-based assays demonstrated the myocardial protective effects and therapeutic potential of NVs. Intramyocardial delivery of NVs in the injured heart after ischemia-reperfusion led to a reduction in scar sizes and preservation of cardiac functions. Such therapeutic benefits are similar to those injected with natural EVs from the same MSC parental cells. In addition, NV therapy promoted angiogenesis and proliferation of cardiomyocytes in the post-injury heart. In summary, extrusion is a highly efficient method to generate a large quantity of therapeutic NVs that can potentially replace extracellular vesicles in regenerative medicine applications.}, number={47}, journal={ACS APPLIED MATERIALS & INTERFACES}, publisher={American Chemical Society (ACS)}, author={Wang, Xianyun and Hu, Shiqi and Li, Junlang and Zhu, Dashuai and Wang, Zhenzhen and Cores, Jhon and Cheng, Ke and Liu, Gang and Huang, Ke}, year={2021}, month={Dec}, pages={55767–55779} }
 @article{li_zhu_hui_bi_yu_huang_hu_wang_caranasos_rossi_et al._2021, title={Injection of ROS-Responsive Hydrogel Loaded with Basic Fibroblast Growth Factor into the Pericardial Cavity for Heart Repair}, volume={31}, ISSN={["1616-3028"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85100498082&partnerID=MN8TOARS}, DOI={10.1002/adfm.202004377}, abstractNote={Abstract Myocardial infarction, among other ischemic heart diseases, is the major cause of mortality and morbidity for patients who have heart diseases. Timely reperfusion of the ischemic myocardium is the most effective way to treat myocardial infarction. However, blood reperfusion to the ischemic tissues leads to an overproduction of toxic reactive oxygen species (ROS), which can further exacerbate myocardial damage on top of ischemic injury. ROS has been used as a diagnostic marker and therapeutic target for ischemia‐reperfusion (I/R) injury and as an environmental stimulus to trigger drug release. In this study, a ROS‐sensitive cross‐linked poly(vinyl alcohol) (PVA) hydrogel is synthesized to deliver basic fibroblast growth factor (bFGF) for myocardial repair. The therapeutic gel is injected into the pericardial cavity. Upon delivery, the hydrogel spread on the surface of the heart and form an epicardiac patch in situ. In a rat model of I/R injury, bFGF released from the gel could penetrate the myocardium. Such intervention protects cardiac function and reduces fibrosis in the post‐I/R heart, with enhanced angiomyogenesis. Furthermore, the safety and feasibility of minimally invasive injection and access into the pericardial cavity in both pigs and human patients are demonstrated.}, number={15}, journal={ADVANCED FUNCTIONAL MATERIALS}, author={Li, Zhenhua and Zhu, Dashuai and Hui, Qi and Bi, Jianing and Yu, Bingjie and Huang, Zhen and Hu, Shiqi and Wang, Zhenzhen and Caranasos, Thomas and Rossi, Joseph and et al.}, year={2021}, month={Apr} }
 @article{zhu_li_huang_caranasos_rossi_cheng_2021, title={Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair}, volume={12}, ISSN={["2041-1723"]}, url={https://doi.org/10.1038/s41467-021-21682-7}, DOI={10.1038/s41467-021-21682-7}, abstractNote={Abstract Cardiac patches are an effective way to deliver therapeutics to the heart. However, such procedures are normally invasive and difficult to perform. Here, we develop and test a method to utilize the pericardial cavity as a natural “mold” for in situ cardiac patch formation after intrapericardial injection of therapeutics in biocompatible hydrogels. In rodent models of myocardial infarction, we demonstrate that intrapericardial injection is an effective and safe method to deliver hydrogels containing induced pluripotent stem cells-derived cardiac progenitor cells or mesenchymal stem cells-derived exosomes. After injection, the hydrogels form a cardiac patch-like structure in the pericardial cavity, mitigating immune response and increasing the cardiac retention of the therapeutics. With robust cardiovascular repair and stimulation of epicardium-derived cells, the delivered therapeutics mitigate cardiac remodeling and improve cardiac functions post myocardial infarction. Furthermore, we demonstrate the feasibility of minimally-invasive intrapericardial injection in a clinically-relevant porcine model. Collectively, our study establishes intrapericardial injection as a safe and effective method to deliver therapeutic-bearing hydrogels to the heart for cardiac repair.}, number={1}, journal={NATURE COMMUNICATIONS}, author={Zhu, Dashuai and Li, Zhenhua and Huang, Ke and Caranasos, Thomas G. and Rossi, Joseph S. and Cheng, Ke}, year={2021}, month={Mar} }
 @article{zhu_hou_qian_jin_hao_pan_wang_wu_liu_wang_et al._2021, title={Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery}, volume={12}, url={https://doi.org/10.1038/s41467-021-24804-3}, DOI={10.1038/s41467-021-24804-3}, abstractNote={Abstract Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. Organic nitrates represent a class of NO-donating drugs for treating coronary artery diseases, acting through the vasodilation of systemic vasculature that often leads to adverse effects. Herein, we design a nitrate-functionalized patch, wherein the nitrate pharmacological functional groups are covalently bound to biodegradable polymers, thus transforming small-molecule drugs into therapeutic biomaterials. When implanted onto the myocardium, the patch releases NO locally through a stepwise biotransformation, and NO generation is remarkably enhanced in infarcted myocardium because of the ischemic microenvironment, which gives rise to mitochondrial-targeted cardioprotection as well as enhanced cardiac repair. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs.}, number={1}, journal={Nature Communications}, author={Zhu, Dashuai and Hou, Jingli and Qian, Meng and Jin, Dawei and Hao, Tian and Pan, Yanjun and Wang, He and Wu, Shuting and Liu, Shuo and Wang, Fei and et al.}, year={2021}, month={Jul} }
 @article{hu_wang_li_zhu_cores_wang_li_mei_cheng_su_et al._2021, title={Platelet membrane and stem cell exosome hybrids enhance cellular uptake and targeting to heart injury}, volume={39}, ISSN={["1878-044X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85107566346&partnerID=MN8TOARS}, DOI={10.1016/j.nantod.2021.101210}, abstractNote={• Platelet membrane modification enhanced the accumulation of exosomes in injured tissues. • Platelet membrane substantially enhanced macropinocytosis-mediated cellular internalization of exosomes. • Platelet membrane hybrid improved the pharmacokinetic of stem cell derived exosomes. • This is a simple, fast, and translatable approach to modify therapeutic exosomes to make them disease targetable. We used platelet membrane to modify exosomes and rely on the natural “injury finding” ability of platelets to target the hybrid exosomes to vascular injury under myocardial infarction. Interestingly, we found that platelet membrane improved cellular binding and internalization of exosomes through enhanced macropinocytosis-mediated cellular internalization by endothelial cells and cardiomyocytes, but not by macrophages. Such modified exosomes showed improved targeting and functional benefits in vitro, and in a mouse myocardial infarction model in vivo, as compared to unmodified naive exosomes. Exosomes from mesenchymal stem cells have been widely studied as therapeutics to treat myocardial infarction. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from endogenous exosomes, and the internalization/clearance by the mononuclear phagocyte system. There is also a lack of targeting. In this study, we hybridized stem cell-derived exosomes with platelet membranes to enhance their ability to target the injured heart and to reduce uptake by macrophages. Furthermore, we found that hybridization with platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes drastically. In vivo studies showed the cardiac targeting ability of hybrid exosomes in a mouse model of myocardial infarction injury. Lastly, we determined cardiac functions and performed immunohistochemistry to confirm an enahnced therapeutic potency of platelet membrane modified exosomes as compared to non-modified exosomes. Our studies provide proof-of-concept data and a universal approach to enhance the binding and accumulation of exosomes in injured tissues.}, journal={NANO TODAY}, author={Hu, Shiqi and Wang, Xianyun and Li, Zhenhua and Zhu, Dashuai and Cores, Jhon and Wang, Zhenzhen and Li, Junlang and Mei, Xuan and Cheng, Xiao and Su, Teng and et al.}, year={2021}, month={Aug} }
 @article{hu_li_shen_zhu_huang_su_dinh_cores_cheng_2021, title={Publisher Correction: Exosome-eluting stents for vascular healing after ischaemic injury}, volume={5}, url={https://doi.org/10.1038/s41551-021-00727-8}, DOI={10.1038/s41551-021-00727-8}, abstractNote={A Correction to this paper has been published: https://doi.org/10.1038/s41551-021-00727-8.}, number={10}, journal={Nature Biomedical Engineering}, author={Hu, Shiqi and Li, Zhenhua and Shen, Deliang and Zhu, Dashuai and Huang, Ke and Su, Teng and Dinh, Phuong-Uyen and Cores, Jhon and Cheng, Ke}, year={2021}, month={Apr}, pages={1239} }
 @article{liu_guo_huang_he_zhu_zhang_peng_che_feng_2020, title={Anti-neuroinflammatory effects of dimethylaminomylide (DMAMCL, i.e., ACT001) are associated with attenuating the NLRP3 inflammasome in MPTP-induced Parkinson disease in mice}, volume={383}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85078981773&partnerID=MN8TOARS}, DOI={10.1016/j.bbr.2020.112539}, abstractNote={Parthenolide (PTL) is a natural compound with anti-inflammatory and antioxidant properties and is an active ingredient extracted from the medicinal plant Tanacetum parthenium. ACT001 is derived from parthenolide and is a fumarate form of dimethylaminomylide (DMAMCL). Its effect is equivalent to that of PTL, but it is more stable in plasma and has lower acquisition costs. Related reports indicate that NLRP3-mediated neuroinflammation is involved in the progression of Parkinson's disease (PD). In our research, we explored whether ACT001 alleviates NLRP3-mediated neuroinflammation in PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results revealed that ACT001 reduces movement impairment and cognitive deficit in PD mice. In addition, it alleviates dopaminergic neurodegeneration in the nigrostriatal pathway and inhibits oxidative stress, the inflammatory response and activation of the NLRP3 inflammasome in the midbrain of MPTP-induced PD mice. Moreover, it attenuates microglial activation in the nigrostriatal pathway. Overall, our study showed that ACT001 alleviates NLRP3-mediated neuroinflammation in PD mice induced by MPTP.}, journal={Behavioural Brain Research}, author={Liu, Q. and Guo, X. and Huang, Z. and He, Q. and Zhu, D. and Zhang, S. and Peng, Z. and Che, Y. and Feng, X.}, year={2020} }
 @article{wang_shang_chen_wang_zhu_liu_zhang_chen_wu_wu_et al._2020, title={Delivery of mscs with a hybrid β-sheet peptide hydrogel consisting igf-1c domain and d-form peptide for acute kidney injury therapy}, volume={15}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85086660555&partnerID=MN8TOARS}, DOI={10.2147/IJN.S254635}, abstractNote={By providing a stem cell microenvironment with particular bioactive constituents in vivo, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. Designs with bioactive motifs to influence cell behavior and with D-form amino acids to modulate scaffold stability may be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy.In this study, we linked naphthalene (Nap) covalently to a short D-form peptide (Nap-DFDFG) and the C domain of insulin-like growth factor-1 (IGF-1C) as a functional hydrogel-based scaffolds, and we hypothesized that this hydrogel could enhance the therapeutic efficiency of human placenta-derived mesenchymal stem cells (hP-MSCs) in a murine acute kidney injury (AKI) model.The self-assembling peptide was constrained into a classical β-sheet structure and showed hydrogel properties. Our results revealed that this hydrogel exhibited increased affinity for IGF-1 receptor. Furthermore, cotransplantation of the β-IGF-1C hydrogel and hP-MSCs contributed to endogenous regeneration post-injury and boosted angiogenesis in a murine AKI model, leading to recovery of renal function.This hydrogel could provide a favorable niche for hP-MSCs and thereby rescue renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional groups to D-form peptides to create functional hydrogels, self-assembling β-sheet peptide hydrogels may serve as a promising platform for tissue-engineering and stem cell therapy.}, journal={International Journal of Nanomedicine}, author={Wang, H. and Shang, Y. and Chen, X. and Wang, Z. and Zhu, D. and Liu, Y. and Zhang, C. and Chen, P. and Wu, J. and Wu, L. and et al.}, year={2020}, pages={4311–4324} }
 @article{zhang_zhang_zhu_jiao_zhao_sun_che_feng_2020, title={Effects of 17β-trenbolone exposure on sex hormone synthesis and social behaviours in adolescent mice}, volume={245}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85076629997&partnerID=MN8TOARS}, DOI={10.1016/j.chemosphere.2019.125679}, abstractNote={17β-Trenbolone (17β-TBOH) is an endocrine disruptor that has been widely reported in aquatic organisms. However, little is known about the effect of 17β-TBOH on mammals, particularly on the development of adolescents. Through a series of behavioural experiments, exposure to at 80 μg kg −1 d −1 and 800 μg kg −1 d −1 17β-TBOH during puberty (from PND 28 to 56, male mice) increased anxiety-like behaviours. Exposure to the low dose of 80 μg kg −1 d −1 resulted in a clear social avoidance behaviour in mice. The two doses affected testicular development and endogenous androgen synthesis in male mice. In addition, 17β-TBOH exposure altered the differentiation of oligodendrocytes and the formation of the myelin sheath in the medial prefrontal cortex (mPFC). These results reveal the effects of 17β-TBOH on the behaviours, gonadal and neurodevelopment of adolescent mammals. In addition, the inhibition of the secretion of endogenous hormones and decrease in the formation of the myelin sheath in mPFC may be associated with the 17β-TBOH-induced behavioural changes in mice.}, journal={Chemosphere}, author={Zhang, S. and Zhang, S. and Zhu, D. and Jiao, Z. and Zhao, X. and Sun, M. and Che, Y. and Feng, X.}, year={2020} }
 @article{liang_li_ren_jia_guo_li_zhang_hu_zhu_shen_et al._2020, title={Light-triggered NO-releasing nanoparticles for treating mice with liver fibrosis}, volume={13}, ISSN={["1998-0000"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85086369757&partnerID=MN8TOARS}, DOI={10.1007/s12274-020-2833-6}, number={8}, journal={NANO RESEARCH}, author={Liang, Hongxia and Li, Zhenhua and Ren, Zhigang and Jia, Qiaodi and Guo, Linna and Li, Shasha and Zhang, Hongyu and Hu, Shiqi and Zhu, Dashuai and Shen, Deliang and et al.}, year={2020}, month={Aug}, pages={2197–2202} }
 @article{midgley_wei_zhu_gao_yan_khalique_luo_jiang_liu_guo_et al._2020, title={Multifunctional natural polymer nanoparticles as antifibrotic gene carriers for CKD therapy}, volume={31}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85092260644&partnerID=MN8TOARS}, DOI={10.1681/ASN.2019111160}, abstractNote={Significance Statement Progressive fibrosis, the underlying pathophysiologic process of CKD, is driven by myofibroblasts and activated profibrotic cells. Treatments targeting these cells for the reversal and amelioration of CKD are lacking. Experimental cytokine therapies administered locally are constrained by low bioavailability and transient activity, but nanoparticles can circumvent this and offer noninvasive kidney-targeted delivery of antifibrotic biologics, such as bone morphogenetic protein 7 (BMP7) and hepatocyte growth factor (HGF)–NK1 (HGF/NK1). The authors used nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI enclosed in biocompatible natural materials for intravenous delivery of gene therapy to CKD mouse models. Delivery of BMP7 reversed the progression of fibrosis and regenerated tubules; delivery of HGF/NK1 halted CKD progression by eliminating collagen fiber deposition. Nanoparticle gene therapy shows potential as a noninvasive approach to treat CKD. Background Progressive fibrosis is the underlying pathophysiological process of CKD, and targeted prevention or reversal of the profibrotic cell phenotype is an important goal in developing therapeutics for CKD. Nanoparticles offer new ways to deliver antifibrotic therapies to damaged tissues and resident cells to limit manifestation of the profibrotic phenotype. Methods We focused on delivering plasmid DNA expressing bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor (HGF)–NK1 (HGF/NK1) by encapsulation within chitosan nanoparticles coated with hyaluronan, to safely administer multifunctional nanoparticles containing the plasmid DNA to the kidneys for localized and sustained expression of antifibrotic factors. We characterized and evaluated nanoparticles in vitro for biocompatibility and antifibrotic function. To assess antifibrotic activity in vivo , we used noninvasive delivery to unilateral ureteral obstruction mouse models of CKD. Results Synthesis of hyaluronan-coated chitosan nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI resulted in consistently sized nanoparticles, which—following endocytosis driven by CD44 + cells—promoted cellular growth and inhibited fibrotic gene expression in vitro . Intravenous tail injection of these nanoparticles resulted in approximately 40%–45% of gene uptake in kidneys in vivo . The nanoparticles attenuated the development of fibrosis and rescued renal function in unilateral ureteral obstruction mouse models of CKD. Gene delivery of BMP7 reversed the progression of fibrosis and regenerated tubules, whereas delivery of HGF/NK1 halted CKD progression by eliminating collagen fiber deposition. Conclusions Nanoparticle delivery of HGF/NK1 conveyed potent antifibrotic and proregenerative effects. Overall, this research provided the proof of concept on which to base future investigations for enhanced targeting and transfection of therapeutic genes to kidney tissues, and an avenue toward treatment of CKD.}, number={10}, journal={Journal of the American Society of Nephrology}, author={Midgley, A.C. and Wei, Y. and Zhu, D. and Gao, F. and Yan, H. and Khalique, A. and Luo, W. and Jiang, H. and Liu, X. and Guo, J. and et al.}, year={2020}, pages={2292–2311} }
 @article{zhang_luo_zhang_zhu_midgley_song_khalique_zhang_zhuang_kong_et al._2020, title={Particle-based artificial three-dimensional stem cell spheroids for revascularization of ischemic diseases}, volume={6}, url={https://doi.org/10.1126/sciadv.aaz8011}, DOI={10.1126/sciadv.aaz8011}, abstractNote={Development of new approaches to biomimetically reconstruct vasculature networks remains challenging in regenerative medicine. We introduce a particle-based artificial stem cell spheroid (ASSP) technology that recapitulates paracrine functions of three-dimensional (3D) SSPs for vasculature regeneration. Specifically, we used a facile method to induce the aggregation of stem cells into 3D spheroids, which benefited from hypoxia microenvironment-driven and enhanced secretion of proangiogenic bioactive factors. Furthermore, we artificially reconstructed 3D spheroids (i.e., ASSP) by integration of SSP-secreted factors into micro-/nanoparticles with cell membrane-derived surface coatings. The easily controllable sizes of the ASSP particles provided superior revascularization effects on the ischemic tissues in hindlimb ischemia models through local administration of ASSP microparticles and in myocardial infarction models via the systemic delivery of ASSP nanoparticles. The strategy offers a promising therapeutic option for ischemic tissue regeneration and addresses issues faced by the bottlenecked development in the delivery of stem cell therapies.}, number={19}, journal={Science Advances}, publisher={American Association for the Advancement of Science (AAAS)}, author={Zhang, Ran and Luo, Wenya and Zhang, Yue and Zhu, Dashuai and Midgley, Adam C. and Song, Hao and Khalique, Anila and Zhang, Haoqi and Zhuang, Jie and Kong, Deling and et al.}, year={2020}, month={May} }
 @article{zhang_shang_chen_midgley_wang_zhu_wu_chen_wu_wang_et al._2020, title={Supramolecular Nanofibers Containing Arginine-Glycine-Aspartate (RGD) Peptides Boost Therapeutic Efficacy of Extracellular Vesicles in Kidney Repair}, volume={14}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85091586638&partnerID=MN8TOARS}, DOI={10.1021/acsnano.0c05681}, abstractNote={Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivo tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV-hydrogel interaction was mediated by RGD-integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.}, number={9}, journal={ACS Nano}, author={Zhang, C. and Shang, Y. and Chen, X. and Midgley, A.C. and Wang, Z. and Zhu, D. and Wu, J. and Chen, P. and Wu, L. and Wang, X. and et al.}, year={2020}, pages={12133–12147} }
 @article{yan_mi_midgley_du_huang_wei_liu_ma_zhi_zhu_et al._2020, title={Targeted Repair of Vascular Injury by Adipose-Derived Stem Cells Modified with P-Selectin Binding Peptide}, volume={7}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85083704027&partnerID=MN8TOARS}, DOI={10.1002/advs.201903516}, abstractNote={Percutaneous coronary intervention for coronary artery disease treatment often results in pathological vascular injury, characterized by P-selectin overexpression. Adipose-derived stem cells (ADSCs) therapeutic efficacy remains elusive due to poor ADSCs targeting and retention in injured vessels. Here, conjugated P-selectin binding peptide (PBP) to polyethylene glycol-conjugated phospholipid derivative (DMPE-PEG) linkers (DMPE-PEG-PBP; DPP) are used to facilitate the modification of PBP onto ADSCs cell surfaces via hydrophobic interactions between DMPE-PEG and the phospholipid bilayer. DPP modification neither has influence on ADSCs proliferation nor apoptosis/paracrine factor gene expression. A total of 5 × 10−6 m DPP-modified ADSCs (DPP-ADSCs) strongly binds to P-selectin-displaying activated platelets and endothelial cells (ECs) in vitro and to wire-injured rat femoral arteries when administered by intra-arterial injection. Targeted binding of ADSCs shields injury sites from platelet and leukocyte adhesion, thereby decreasing inflammation at injury sites. Furthermore, targeted binding of ADSCs recovers injured ECs functionality and reduces platelet-initiated vascular smooth muscle cells (VSMCs) chemotactic migration. Targeted binding of DPP-human ADSCs to balloon-injured human femoral arteries is also demonstrated in ex vivo experiments. Overall, DPP-ADSCs promote vascular repair, inhibit neointimal hyperplasia, increase endothelium functionality, and maintain normal VSMCs alignment, supporting preclinical noninvasive utilization of DPP-ADSCs for vascular injury.}, number={11}, journal={Advanced Science}, author={Yan, H. and Mi, X. and Midgley, A.C. and Du, X. and Huang, Z. and Wei, T. and Liu, R. and Ma, T. and Zhi, D. and Zhu, D. and et al.}, year={2020} }
 @article{liu_zhang_zhu_tang_che_feng_2020, title={The parthenolide derivative ACT001 synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson's disease in mice}, volume={379}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85075482549&partnerID=MN8TOARS}, DOI={10.1016/j.bbr.2019.112337}, abstractNote={L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the main drug used to treat Parkinson's disease (PD). However, long-term use of l-DOPA causes substantial side effects, and we hope to find a biological active ingredient that synergizes with a low-dose of l-DOPA to achieve the same therapeutic effect as that of a high-dose of l-DOPA. The natural product parthenolide (PTL) is the active ingredient in the medicinal plant feverfew (Tanacetum parthenium) and has antioxidant and anti-inflammatory properties. ACT001, a fumarate salt form of dimethylaminomicheliolide (DMAMCL), is a derivative of parthenolide and has comparable effects to those of PTL but exhibits higher stability in the plasma and is available at a lower cost. In our study, we used ACT001 in combination with l-DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Specifically, ACT001 significantly reduced motor dysfunction and dopaminergic neurodegeneration in MPTP-treated mice. Furthermore, ACT001 abolished MPTP-induced α-synuclein overexpression, astrocyte activation and interleukin-1β (IL-1β) production in the substantia nigra and striatum of the mouse brain. In addition, ACT001 increased the levels of the anti-apoptotic signalling molecule Bcl-2 and the pAkt/Akt ratio and reduced the levels of the pro-apoptotic signalling molecule Bax and the activation of Caspase3 in the substantia nigra and striatum. We found that the effects of the co-administration of ACT001 and l-DOPA (5 mg/kg) were equivalent to those of the administration of 8 mg/kg l-DOPA in MPTP-induced Parkinson's disease in mice. Then, this evidence suggests that l-DOPA + ACT001 may be used for the treatment of PD.}, journal={Behavioural Brain Research}, author={Liu, Q. and Zhang, S. and Zhu, D. and Tang, X. and Che, Y. and Feng, X.}, year={2020} }
 @article{zhang_zhu_wei_wu_cui_liuqin_fan_yang_wang_xu_et al._2019, title={A collagen hydrogel loaded with HDAC7-derived peptide promotes the regeneration of infarcted myocardium with functional improvement in a rodent model}, volume={86}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85060326213&partnerID=MN8TOARS}, DOI={10.1016/j.actbio.2019.01.022}, abstractNote={Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle (LV) dilation, and cardiac dysfunction, eventually developing into heart failure. Most of the strategies for MI therapy require biomaterials that can support tissue regeneration. In this study, we hypothesized that the extracellular matrix (ECM)-derived collagen I hydrogel loaded with histone deacetylase 7 (HDAC7)-derived-phosphorylated 7-amino-acid peptide (7Ap) could restrain LV remodeling and improve cardiac function after MI. An MI model was established by ligation of the left anterior descending coronary artery (LAD) of C57/B6 mice. The 7Ap-loaded collagen I hydrogel was intramyocardially injected to the infarcted region of the LV wall of the heart. After local delivery, the 7Ap-collagen increased neo-microvessel formation, enhanced stem cell antigen-1 positive (Sca-1+) stem cell recruitment and differentiation, decreased cellular apoptosis, and promoted cardiomyocyte cycle progression. Furthermore, the 7Ap-collagen restricted the fibrosis of the LV wall, reduced the infarct wall thinning, and improved cardiac performance significantly at 2 weeks post-MI. These results highlight the promising implication of 7Ap-collagen as a novel candidate for MI therapy. The mammalian myocardium has a limited regenerative capability following myocardial infarction (MI). MI leads to extensive loss of cardiomyocytes, thus culminating in adverse cardiac remodeling and congestive heart failure. In situ tissue regeneration through endogenous cell mobilization has great potential for tissue regeneration. A 7-amino-acid-peptide (7A) domain encoded by a short open-reading frame (sORF) of the HDAC7 gene. The phosphorylated from of 7A (7Ap) has been reported to promote in situ tissue repair via the mobilization and recruitment of endogenous stem cell antigen-1 positive (Sca-l+) stem cells. In this study, 7Ap was shown to improve H9C2 cell survival, in vitro. In vivo investigations in a mouse MI model demonstrated that intra-myocardial delivery of 7Ap-loaded collagen hydrogel promoted neovascularization, stimulated Sca-l+ stem cell recruitment and differentiation, reduced cardiomyocyte apoptosis and promoted cell cycle progression. As a result, treated infarcted hearts had increased wall thickness, had improved heart function and exhibited attenuation of adverse cardiac remodeling, observed for up to 2 weeks. Overall, these results highlighted the positive impact of implanting 7Ap-collagen as a novel constituent for MI repair.}, journal={Acta Biomaterialia}, author={Zhang, Y. and Zhu, D. and Wei, Y. and Wu, Y. and Cui, W. and Liuqin, L. and Fan, G. and Yang, Q. and Wang, Z. and Xu, Z. and et al.}, year={2019}, pages={223–234} }
 @article{wang_shang_chen_wang_zhu_liu_zhang_chen_wu_wu_et al._2019, title={Delivery of MSCs with a Hybrid β-Sheet Peptide Hydrogel Consisting IGF-1C Domain and D-Form Peptide for Acute Kidney Injury Therapy}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85109309821&partnerID=MN8TOARS}, DOI={10.2139/ssrn.3485132}, abstractNote={By providing an appropriate microenvironment, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. The designs with bioactive motifs to influence cell behavior and with D-form amino acid to modulate scaffold stability will be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy. In this study, we linked naphthalene (Nap) covalently conjugated a short D-form peptide (Nap-DFDFG) to C domain of insulin-like growth factor-1 (IGF-1C) as a functional peptide-based scaffold. Our purpose is to provide a functional self-assembling peptide hydrogel with encapsulated human placenta derived mesenchymal stem cells (hP-MSCs) and thereby to enhance the therapeutic efficiency of hP-MSCs in murine acute kidney injury (AKI) model. Our results revealed that a typical β-sheet conformation was confirmed and this self-assembling peptide hydrogel exhibited higher affinity with IGF-1 receptor. Furthermore, this hydrogel could provide a favorable niche for hP-MSCs and thereby ameliorate renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional group to D-form peptide to create a functional hydrogel, this self-assembling β-sheet peptide hydrogel will serve as a promising platform for future tissue-engineering and stem cell therapy.}, journal={SSRN}, author={Wang, H. and Shang, Y. and Chen, X. and Wang, Z. and Zhu, D. and Liu, Y. and Zhang, C. and Chen, P. and Wu, J. and Wu, L. and et al.}, year={2019} }
 @article{qi_li_yun_zhang_huang_zhou_yan_wei_liu_zhang_et al._2019, title={Lactobacillus maintains healthy gut mucosa by producing L-Ornithine}, volume={2}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85070997928&partnerID=MN8TOARS}, DOI={10.1038/s42003-019-0424-4}, abstractNote={Gut mucosal layers are crucial in maintaining the gut barrier function. Gut microbiota regulate homeostasis of gut mucosal layer via gut immune cells such as RORγt (+) IL-22(+) ILC3 cells, which can influence the proliferation of mucosal cells and the production of mucin. However, it is unclear how gut microbiota execute this regulation. Here we show that lactobacilli promote gut mucosal formation by producing L-Ornithine from arginine. L-Ornithine increases the level of aryl hydrocarbon receptor ligand L-kynurenine produced from tryptophan metabolism in gut epithelial cells, which in turn increases RORγt (+)IL-22(+) ILC3 cells. Human REG3A transgenic mice show an increased proportion of L-Ornithine producing lactobacilli in the gut contents, suggesting that gut epithelial REG3A favors the expansion of L-Ornithine producing lactobacilli. Our study implicates the importance of a crosstalk between arginine metabolism in Lactobacilli and tryptophan metabolism in gut epithelial cells in maintaining gut barrier.}, number={1}, journal={Communications Biology}, author={Qi, H. and Li, Y. and Yun, H. and Zhang, T. and Huang, Y. and Zhou, J. and Yan, H. and Wei, J. and Liu, Y. and Zhang, Z. and et al.}, year={2019} }
 @article{li_liu_zhu_che_feng_2019, title={Preparation of levodopa-loaded crystalsomes through thermally induced crystallization reverses functional deficits in Parkinsonian mice}, volume={7}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85063456111&partnerID=MN8TOARS}, DOI={10.1039/c8bm01098f}, abstractNote={The prepared levodopa loaded crystalsomes are nanoscale crystals and controlling levodopa release which improving MPTP-induced behavioral impairments and pathological features of mice.}, number={4}, journal={Biomaterials Science}, author={Li, X. and Liu, Q. and Zhu, D. and Che, Y. and Feng, X.}, year={2019}, pages={1623–1631} }
 @article{liu_zhu_jiang_tang_lang_yu_zhang_che_feng_2019, title={Resveratrol synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson disease in mice}, volume={367}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85063438332&partnerID=MN8TOARS}, DOI={10.1016/j.bbr.2019.03.043}, abstractNote={L-DOPA (L-3,4-dihydroxyphenylalanine) relieves symptoms of Parkinson disease (PD), but long-term use can cause serious side effects. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RV), a polyphenolic compound derived from grapes and red wine that has antioxidant activity, has been shown to have neuroprotective effects. RV was investigated to enhance the therapeutic effect of L-DOPA in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson disease. Mice received a saline or RV injection (10 mg/kg/day), then 2 h later, saline or MPTP (15 mg/kg/day) was administered for 7 consecutive days. Saline or L-DOPA (5 or 8 mg/kg/day) was injected post-administration of MPTP for the last 2 consecutive days. Our results indicated that RV alleviated MPTP-induced loss of dopaminergic neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, RV reduced the expression of α-synuclein in the striatum. In addition, RV also increased levels of the anti-apoptotic signalling molecule Bcl-2, reduced levels of the pro-apoptotic signalling molecule Bax, and reduced activation of caspase-3 in the striatum. Specifically, RV significantly reduced motor dysfunction in MPTP-treated mice. Furthermore, the RV-treated group showed less IL-1β and an enhanced pAkt/Akt ratio, which promoted dopamine neuron survival in the striatum. We found that the effects of co-administration of RV with L-DOPA (5 mg/kg) were equivalent to those of administration of 8 mg/kg L-DOPA in MPTP-induced PD mice. Therefore, with fewer side effects, L-DOPA can be effectively used in the treatment of PD over a long period of time.}, journal={Behavioural Brain Research}, author={Liu, Q. and Zhu, D. and Jiang, P. and Tang, X. and Lang, Q. and Yu, Q. and Zhang, S. and Che, Y. and Feng, X.}, year={2019}, pages={10–18} }
 @article{hou_pan_zhu_fan_feng_wei_wang_qin_zhao_yang_et al._2019, title={Targeted delivery of nitric oxide via a ‘bump-and-hole’-based enzyme–prodrug pair}, volume={15}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85059459174&partnerID=MN8TOARS}, DOI={10.1038/s41589-018-0190-5}, number={2}, journal={Nature Chemical Biology}, author={Hou, J. and Pan, Y. and Zhu, D. and Fan, Y. and Feng, G. and Wei, Y. and Wang, H. and Qin, K. and Zhao, T. and Yang, Q. and et al.}, year={2019}, pages={151–160} }
 @article{feng_li_zhu_zhang_song_zhang_chen_du_yao_2018, title={Expression and clinical significance of CXC-chemokine ligand 5 in renal cell carcinoma}, volume={45}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85061286356&partnerID=MN8TOARS}, DOI={10.3969/j.issn.1000-8179.2018.16.636}, number={16}, journal={Chinese Journal of Clinical Oncology}, author={Feng, G. and Li, H. and Zhu, D. and Zhang, Y. and Song, G. and Zhang, Z. and Chen, M. and Du, J. and Yao, X.}, year={2018}, pages={838–843} }
 @article{shafiq_zhang_zhu_zhao_kim_kim_kong_2018, title={In situ cardiac regeneration by using neuropeptide substance P and IGF-1C peptide eluting heart patches}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85073764097&partnerID=MN8TOARS}, DOI={10.1093/rb/rby021}, abstractNote={Cardiovascular diseases cause huge socio-economic burden worldwide. Although a mammalian myocardium has its own limited healing capability, scaffold materials capable of releasing stem cell recruiting/engrafting factors may facilitate the regeneration of the infarcted myocardium. The aim of this research was to develop cardiac patches capable of simultaneously eluting substance P (SP) and insulin-like growth factor-1C (IGF-1C) peptide. Polycaprolactone/collagen type 1-based patches with or without SP and IGF-1C peptide were fabricated by co-electrospinning, which exhibited nanofibrous morphology. SP and IGF-1C/SP patches recruited significantly higher numbers of bone marrow-mesenchymal stem cells than that of the negative control and patch-only groups in vitro. The developed patches were transplanted in an infarcted myocardium for up to 14 days. Mice underwent left anterior descending artery ligation and received one of the following treatments: (i) sham, (ii) saline, (iii) patch-only, (iv) IGF-1C patch, (v) SP patch and (vi) IGF-1C/SP patch. SP and IGF-1C/SP patch-treated groups exhibited better heart function and attenuated adverse cardiac remodeling than that of the saline, patch-only and individual peptide containing cardiac patches. SP patch and IGF-1C/SP patch-treated groups also showed higher numbers of CD31-positive vessels and isolectin B4-positive capillaries than that of other groups. IGF-1C/SP-treated group also showed thicker left ventricular wall in comparison to the saline and patch-only groups. Moreover, IGF-1C/SP patches recruited significantly higher numbers of CD29-positive cells and showed less numbers of Tunel-positive cells compared with the other groups. These data suggest that SP and IGF-1C peptides may act synergistically for in situ tissue repair.}, number={5}, journal={Regenerative Biomaterials}, author={Shafiq, M. and Zhang, Y. and Zhu, D. and Zhao, Z. and Kim, D.-H. and Kim, S.H. and Kong, D.}, year={2018}, pages={303–316} }
 @article{zhang_liu_zhang_zhu_qi_cao_fang_che_han_he_et al._2018, title={Prostaglandin E<sub>2</sub> hydrogel improves cutaneous wound healing via M2 macrophages polarization}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85056754206&partnerID=MN8TOARS}, DOI={10.7150/thno.27385}, abstractNote={Wound healing is regulated by a complex series of events and overlapping phases. A delicate balance of cytokines and mediators in tissue repair is required for optimal therapy in clinical applications. Molecular imaging technologies, with their versatility in monitoring cellular and molecular events in living organisms, offer tangible options to better guide tissue repair by regulating the balance of cytokines and mediators at injured sites. Methods: A murine cutaneous wound healing model was developed to investigate if incorporation of prostaglandin E2 (PGE2) into chitosan (CS) hydrogel (CS+PGE2 hydrogel) could enhance its therapeutic effects. Bioluminescence imaging (BLI) was used to noninvasively monitor the inflammation and angiogenesis processes at injured sites during wound healing. We also investigated the M1 and M2 paradigm of macrophage activation during wound healing. Results: CS hydrogel could prolong the release of PGE2, thereby improving its tissue repair and regeneration capabilities. Molecular imaging results showed that the prolonged release of PGE2 could ameliorate inflammation by promoting the M2 phenotypic transformation of macrophages. Also, CS+PGE2 hydrogel could augment angiogenesis at the injured sites during the early phase of tissue repair, as revealed by BLI. Furthermore, our results demonstrated that CS+PGE2 hydrogel could regulate the balance among the three overlapping phases-inflammation, regeneration (angiogenesis), and remodeling (fibrosis)-during cutaneous wound healing. Conclusion: Our findings highlight the potential of the CS+PGE2 hydrogel as a novel therapeutic strategy for promoting tissue regeneration via M2 macrophage polarization. Moreover, molecular imaging provides a platform for monitoring cellular and molecular events in real-time during tissue repair and facilitates the discovery of optimal therapeutics for injury repair by regulating the balance of cytokines and mediators at injured sites.}, number={19}, journal={Theranostics}, author={Zhang, S. and Liu, Y. and Zhang, X. and Zhu, D. and Qi, X. and Cao, X. and Fang, Y. and Che, Y. and Han, Z.-C. and He, Z.-X. and et al.}, year={2018}, pages={5348–5361} }
 @article{li_wei_li_zhu_nie_zhou_lou_dong_wu_che_et al._2017, title={Herbal formula Xian-Fang-Huo-Ming-Yin regulates differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis mice}, volume={17}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85008397816&partnerID=MN8TOARS}, DOI={10.1186/s12906-016-1526-x}, abstractNote={Xian-Fang-Huo-Ming-Yin (XFHM), a traditional herbal formula, has been used to treat sores and carbuncles for hundreds of years in Asia. Nowadays, its clinical effects in treatment of rheumatoid arthritis (RA) have been validated. In this study, we want to study its possible molecular mechanisms of regulating the differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis (CIA) mice for RA treatment. A high performance liquid chromatography-electrospray ionization/mass spectrometer (HPLC-ESI/MSn) system was used to analyze the constituents of XFHM granules. An arthritics mouse model was induced by collagen and leflunomide (LEF) was used as a positive control medicine. Pathological changes at the metatarsophalangeal joint were studied through Safranin O and immunohistochemical staining. The differentiation of T, B and NK cells was examined by flow cytometry and pro-inflammatory cytokines were assayed using an Inflammation Antibody Array assay. The expression of key molecules of the nuclear factor κB (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in spleen were studied by western-blot analysis. In our study. 21 different dominant chemical constituents were identified in XFHM. Treatment with XFHM suppressed the pathological changes in arthrosis of CIA. Additionally, XFHM down-regulated the proliferation and differentiation of CD3+ T cells and CD3−CD19+ B cells significantly. However, XFHM had no significant effect on CD3−NK1.1+ NK cells. Further study showed that the production of pro-inflammatory cytokines had been suppressed by inhibiting the activation of NF-κB and JAK/STAT signaling. XFHM can regulate and maintain the immunologic balance of lymphocytic immunity and inhibit the production of pro-inflammatory cytokines, thus suppressing the pathological changes of RA. Therefore, XFHM may be used as an application of traditional medicine against RA in modern complementary and alternative therapeutics.}, number={1}, journal={BMC Complementary and Alternative Medicine}, author={Li, J. and Wei, Y. and Li, X. and Zhu, D. and Nie, B. and Zhou, J. and Lou, L. and Dong, B. and Wu, A. and Che, Y. and et al.}, year={2017} }
 @article{li_sun_li_zhu_jia_jiao_wang_kong_zhao_xu_et al._2017, title={PEGylation corannulene enhances response of stress through promoting neurogenesis}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85016312774&partnerID=MN8TOARS}, DOI={10.1039/c7bm00068e}, abstractNote={The synthesized PEGylation corannulene nanoparticles was examined in neural functions, which have effects on improving behavioral response to stress and promoting neurogenesis.}, number={4}, journal={Biomaterials Science}, author={Li, X. and Sun, D. and Li, X. and Zhu, D. and Jia, Z. and Jiao, J. and Wang, K. and Kong, D. and Zhao, X. and Xu, L. and et al.}, year={2017}, pages={849–859} }
 @article{li_ma_xu_zhu_li_che_chen_feng_2017, title={Puerarin and Amlodipine Improvement of d-Galactose-Induced Impairments of Behaviour and Neurogenesis in Mouse Dentate Gyrus: Correlation with Glucocorticoid Receptor Expression}, volume={42}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85027870475&partnerID=MN8TOARS}, DOI={10.1007/s11064-017-2366-x}, number={11}, journal={Neurochemical Research}, author={Li, X.Y. and Ma, J. and Xu, J. and Zhu, D.S. and Li, A. and Che, Y.Z. and Chen, D.Y. and Feng, X.Z.}, year={2017}, pages={3268–3278} }
 @article{jia_yang_jiao_li_zhu_yang_yang_che_lu_feng_2017, title={Rhein and polydimethylsiloxane functionalized carbon/carbon composites as prosthetic implants for bone repair applications}, volume={12}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85029145036&partnerID=MN8TOARS}, DOI={10.1088/1748-605X/aa6e27}, abstractNote={A major issue in bone tissue engineering is the selection of biocompatible materials for implants, to reduce unwanted inflammatory reactions and promote cell adhesion. Bone tissue growth on suitable biomedical implants can shorten recovery and hospitalization after surgery. Therefore, a method to improve tissue–implant integration and healing would be of scientific and clinical interest. In this work, we permeated polydimethylsiloxane (PDMS) into carbon/carbon (C/C) composites (PDMS–C/C) and then coated it with 4,5-dihydroxyanthraquinone-2-carboxylic acid (rhein) to create rhein–PDMS–C/C to increase its biocompatibility and reduce the occurrence of inflammatory reactions. We measured in vitro adhesion and proliferation of MC3T3-E1 cells and bacteria to evaluate the biocompatibility and antimicrobial properties of C/C, PDMS–C/C, and rhein–PDMS–C/C. In vivo, x-ray and micro-CT evaluation three, six and nine weeks after surgery revealed that rhein–PDMS–C/C was more effective than PDMS–C/C and C/C composite in terms of antibacterial activity, cell adhesion and tissue growth. Compared with C/C and PDMS–C/C, rhein–PDMS–C/C could be suitable for clinical applications for bone tissue engineering.}, number={4}, journal={Biomedical Materials (Bristol)}, author={Jia, Z. and Yang, C. and Jiao, J. and Li, X. and Zhu, D. and Yang, Y. and Yang, J. and Che, Y. and Lu, Y. and Feng, X.}, year={2017} }
 @article{feng_zhang_li_nie_zhu_wang_liu_gao_liu_he_et al._2016, title={IGF-1 C domain-modified hydrogel enhances cell therapy for AKI}, volume={27}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84975522975&partnerID=MN8TOARS}, DOI={10.1681/ASN.2015050578}, abstractNote={Low cell retention and engraftment after transplantation limit the successful application of stem cell therapy for AKI. Engineered microenvironments consisting of a hydrogel matrix and growth factors have been increasingly successful in controlling stem cell fate by mimicking native stem cell niche components. Here, we synthesized a bioactive hydrogel by immobilizing the C domain peptide of IGF-1 (IGF-1C) on chitosan, and we hypothesized that this hydrogel could provide a favorable niche for adipose-derived mesenchymal stem cells (ADSCs) and thereby enhance cell survival in an AKI model. In vitro studies demonstrated that compared with no hydrogel or chitosan hydrogel only, the chitosan-IGF-1C hydrogel increased cell viability through paracrine effects. In vivo, cotransplantation of the chitosan-IGF-1C hydrogel and ADSCs in ischemic kidneys ameliorated renal function, likely by the observed promotion of stem cell survival and angiogenesis, as visualized by bioluminescence imaging and attenuation of fibrosis. In conclusion, IGF-1C immobilized on a chitosan hydrogel provides an artificial microenvironment for ADSCs and may be a promising therapeutic approach for AKI.}, number={8}, journal={Journal of the American Society of Nephrology}, author={Feng, G. and Zhang, J. and Li, Y. and Nie, Y. and Zhu, D. and Wang, R. and Liu, J. and Gao, J. and Liu, N. and He, N. and et al.}, year={2016}, pages={2357–2369} }