@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{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={AbstractThe stromal‐derived factor 1α/chemokine receptor 4 (SDF‐1α/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‐1α‐encapsulated Puerarin (PUE) hydrogel (SDF‐1α@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‐1α@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{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{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={
            Background:
            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.
          
          
            Methods:
            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.
          
          
            Results:
            
              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.
            
          
          
            Conclusions:
            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={https://doi.org/10.1016/j.cej.2021.131581}, 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{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{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={Cardiac 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.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 with two small incisions and can be refilled multiple times with the therapeutic of choice.We 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 paracrine factors to the infarcted site for cardiac repair.In 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 with two small incisions and can be refilled with the therapeutic of choice.}, 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} }
 @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. Exosome-eluting stents implanted in rats after ischaemic injury accelerate vascular healing and promote tissue regeneration.}, 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{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={AbstractMyocardial 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={AbstractCardiac 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{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={Exosomes from mesenchymal stem cells have been largely studied as therapeutics to treat myocardial infarctions. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from exosomes already in circulation, and the internalization/clearance by the mononuclear phagocyte system. In this study, we hybrid exosomes with platelet membranes to enhance their ability to target the injured heart and avoid being captured by macrophages. Furthermore, we found that encapsulation by the platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes strikingly. In vivo studies showed that the cardiac targeting ability of hybrid exosomes in a mice model with myocardial infarction injury. Last, we tested cardiac functions and performed immunohistochemistry to confirm a better therapeutic effect of platelet membrane modified exosomes 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{su_huang_mathews_scharf_hu_li_frame_cores_dinh_daniele_et al._2020, title={Cardiac Stromal Cell Patch Integrated with Engineered Microvessels Improves Recovery from Myocardial Infarction in Rats and Pigs}, volume={6}, ISSN={["2373-9878"]}, DOI={10.1021/acsbiomaterials.0c00942}, abstractNote={The vascularized cardiac patch strategy is promising for ischemic heart repair after myocardial infarction (MI), but current fabrication processes are quite complicated. Vascularized cardiac patches that can promote concurrent restoration of both the myocardium and vasculature at the injured site in a large animal model remain elusive. The safety and therapeutic benefits of a cardiac stromal cell patch integrated with engineered biomimetic microvessels (BMVs) were determined for treating MI. By leveraging a microfluidic method employing hydrodynamic focusing, we constructed the endothelialized microvessels and then encapsulated them together with therapeutic cardiosphere-derived stromal cells (CSCs) in a fibrin gel to generate a prevascularized cardiac stromal cell patch (BMV-CSC patch). We showed that BMV-CSC patch transplantation significantly promoted cardiac function, reduced scar size, increased viable myocardial tissue, promoted neovascularization, and suppressed inflammation in rat and porcine MI models, demonstrating enhanced therapeutic efficacy compared to conventional cardiac stromal cell patches. BMV-CSC patches did not increase renal and hepatic toxicity or exhibit immunogenicity. We noted a significant increase in endogenous progenitor cell recruitment to the peri-infarct region of the porcine hearts treated with BMV-CSC patch as compared to those that received control treatments. These findings establish the BMV-CSC patch as a novel engineered-tissue therapeutic for ischemic tissue repair.}, number={11}, journal={ACS BIOMATERIALS SCIENCE & ENGINEERING}, author={Su, Teng and Huang, Ke and Mathews, Kyle G. and Scharf, Valery F. and Hu, Shiqi and Li, Zhenhua and Frame, Brianna N. and Cores, Jhon and Dinh, Phuong-Uyen and Daniele, Michael A. and et al.}, year={2020}, month={Nov}, pages={6309–6320} }
 @article{hu_li_lutz_huang_su_cores_dinh_cheng_2020, title={Dermal exosomes containing miR-218-5p promote hair regeneration by regulating beta-catenin signaling}, volume={6}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aba1685}, DOI={10.1126/sciadv.aba1685}, abstractNote={Exosomes derived from dermal papilla spheroids express a high level of miR-218-5p, which directly regulates hair regeneration.}, number={30}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Hu, Shiqi and Li, Zhenhua and Lutz, Halle and Huang, Ke and Su, Teng and Cores, Jhon and Dinh, Phuong-Uyen Cao and Cheng, Ke}, year={2020}, month={Jul} }
 @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{zheng_fan_liu_zhang_dai_li_zhou_hu_yang_jin_et al._2021, title={Self-Propelled and Near-Infrared-Phototaxic Photosynthetic Bacteria as Photothermal Agents for Hypoxia-Targeted Cancer Therapy}, volume={15}, ISBN={1936-086X}, DOI={10.1021/acsnano.0c08068}, abstractNote={Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an "all-in-one" manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.}, number={1}, journal={ACS NANO}, author={Zheng, Pengli and Fan, Miao and Liu, Huifang and Zhang, Yinghua and Dai, Xinyue and Li, Hang and Zhou, Xiaohan and Hu, Shiqi and Yang, Xinjian and Jin, Yi and et al.}, year={2021}, pages={1100–1110} }
 @article{li_hu_huang_su_cores_cheng_2020, title={Targeted anti-IL-1 beta platelet microparticles for cardiac detoxing and repair}, volume={6}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aay0589}, DOI={10.1126/sciadv.aay0589}, abstractNote={Platelet microparticles are used to deliver IL-1β antibodies to myocardial infarction for cardiac detoxing and repair.}, number={6}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Li, Zhenhua and Hu, Shiqi and Huang, Ke and Su, Teng and Cores, Jhon and Cheng, Ke}, year={2020}, month={Feb} }
 @article{qiao_hu_huang_su_li_vandergriff_cores_dinh_allen_shen_et al._2020, title={Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs}, volume={10}, ISSN={["1838-7640"]}, DOI={10.7150/thno.39434}, abstractNote={Cancer is the second leading cause of death worldwide and patients are in urgent need of therapies that can effectively target cancer with minimal off-target side effects. Exosomes are extracellular nano-shuttles that facilitate intercellular communication between cells and organs. It has been established that tumor-derived exosomes contain a similar protein and lipid composition to that of the cells that secrete them, indicating that exosomes might be uniquely employed as carriers for anti-cancer therapeutics. Methods: We isolated exosomes from two cancer cell lines, then co-cultured each type of cancer cells with these two kinds of exosomes and quantified exosome. HT1080 or Hela exosomes were systemically injected to Nude mice bearing a subcutaneous HT1080 tumor to investigate their cancer-homing behavior. Moreover, cancer cell-derived exosomes were engineered to carry Doxil (a common chemotherapy drug), known as D-exo, were used to detect their target and therapeutic efficacy as anti-cancer drugs. Exosome proteome array analysis were used to reveal the mechanism underly this phenomenon. Results: Exosomes derived from cancer cells fuse preferentially with their parent cancer cells, in vitro. Systemically injected tumor-derived exosomes home to their original tumor tissues. Moreover, compared to Doxil alone, the drug-loaded exosomes showed enhanced therapeutic retention in tumor tissues and eradicated them more effectively in nude mice. Exosome proteome array analysis revealed distinct integrin expression patterns, which might shed light on the underlying mechanisms that explain the exosomal cancer-homing behavior. Conclusion: Here we demonstrate that the exosomes' ability to target the parent cancer is a phenomenon that opens up new ways to devise targeted therapies to deliver anti-tumor drugs.}, number={8}, journal={THERANOSTICS}, author={Qiao, Li and Hu, Shiqi and Huang, Ke and Su, Teng and Li, Zhenhua and Vandergriff, Adam and Cores, Jhon and Dinh, Phuong-Uyen and Allen, Tyler and Shen, Deliang and et al.}, year={2020}, pages={3474–3487} }
 @article{shen_li_hu_huang_su_liang_liu_cheng_2019, title={Antibody-Armed Platelets for the Regenerative Targeting of Endogenous Stem Cells}, volume={19}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.8b04970}, abstractNote={Stem cell therapies have shown promise in treating acute and chronic ischemic heart disease. However, current therapies are limited by the low retention and poor integration of injected cells in the injured tissue. Taking advantage of the natural infarct-homing ability of platelets, we engineered CD34 antibody-linked platelets (P-CD34) to capture circulating CD34-positive endogenous stem cells and direct them to the injured heart. In vitro, P-CD34 could bind to damaged aortas and capture endogenous stem cells in whole blood. In a mouse model of acute myocardial infarction, P-CD34 accumulated in the injured heart after intravenous administration, leading to a concentration of endogenous CD34 stem cells in the injured heart for effective heart repair. This represents a new technology for endogenous stem cell therapy.}, number={3}, journal={NANO LETTERS}, author={Shen, Deliang and Li, Zhenhua and Hu, Shiqi and Huang, Ke and Su, Teng and Liang, Hongxia and Liu, Feiran and Cheng, Ke}, year={2019}, month={Mar}, pages={1883–1891} }
 @article{huang_li_su_shen_hu_cheng_2019, title={Bispecific Antibody Therapy for Effective Cardiac Repair through Redirection of Endogenous Stem Cells}, volume={2}, ISSN={["2366-3987"]}, DOI={10.1002/adtp.201900009}, abstractNote={AbstractBone marrow stem cells (BMSCs) are a promising strategy for cardiac regenerative therapy for myocardial infarction (MI). However, cell transplantation has to overcome a number of hurdles, such as cell quality control, clinical practicality, low cell retention/engraftment, and immune reactions when allogeneic cells are used. Bispecific antibodies (BsAbs) have been developed as potential agents in cancer immunotherapy but their application is sparse in cardiovascular diseases. In the present study, BsAbs are designed by chemical cycloaddition of F(ab′)2 fragments from monoclonal anti‐CD34 and anti‐ cardiac myosin heavy chain (CMHC) antibodies, which specifically targets circulating CD34‐positive cells and injured cardiomyocytes simultaneously. It is hypothesized that intravenous administration of stem cell re‐directing (SCRD) BsAbs (anti‐CD34‐F(ab′)2–anti‐CMHC‐F(ab′)2) can home endogenous BMSCs to the injured heart for cardiac repair. The in vivo studies in a mouse model with heart ischemia/reperfusion (I/R) injury demonstrate the safety and therapeutic potency of SCRD BsAb, which supports cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function.}, number={10}, journal={ADVANCED THERAPEUTICS}, author={Huang, Ke and Li, Zhenhua and Su, Teng and Shen, Deliang and Hu, Shiqi and Cheng, Ke}, year={2019}, month={Oct} }
 @misc{li_hu_cheng_2019, title={Chemical Engineering of Cell Therapy for Heart Diseases}, volume={52}, ISSN={["1520-4898"]}, DOI={10.1021/acs.accounts.9b00137}, abstractNote={Cardiovascular disease (CVD) is a major health problem worldwide. Since adult cardiomyocytes irreversibly withdraw from the cell cycle soon after birth, it is hard for cardiac cells to proliferate and regenerate after myocardial injury, such as that caused myocardial infarction (MI). Live cell-based therapies, which we term as first generation of therapeutic strategies, have been widely used for the treatment of many diseases, including CVD. However, cellular approaches have the problems of poor retention of the transplanted cells and the significant entrapment of the cells in the lungs when delivered intravenously. Another big problem is the low storage/shipping stability of live cells, which limits the manufacturability of living cell products. The field of chemical engineering focuses on designing large-scale processes to convert chemicals, raw materials, living cells, microorganisms, and energy into useful forms and products. By definition, chemical engineers conceive and design processes to produce, transform, and transport materials. This matches the direction that cell therapies are heading toward: "produce", from live cells to synthetic artificial cells; "transform", from bare cells to cell/matrix/factor combinations; and "transport". from simple systemic injections to targeted delivery. Thus, we hereby introduce the "chemical engineering of cell therapies" as a concept. In this Account, we summarize our recent efforts to develop chemical engineering approaches to repair injured hearts. To address the limitations of poor cellular retention and integration, the first step was the artificial manipulation of stem cells before injections (we term this the second generation of therapeutic strategies). For example, we took advantage of the natural infarct-targeting ability of platelet membranes by fusing them onto the surface of cardiac stromal/stem cells (CSCs). By doing so, we improved the rate at which they were delivered through the vasculature to sites of MI. In addition to modifying natural CSCs, we described a bioengineering approach that involved the encapsulation of CSCs in a polymeric microneedle patch for myocardium regeneration. The painless microneedle patches were used as an in situ delivery device, which directly transported the loaded CSCs to the MI heart. In addition to low cell retention, there are some other barriers that need to be addressed before further clinical application is viable, including the storage/shipping stability of and the evident safety concerns about live cells. Therefore, we developed the third generation of therapeutic strategies, which utilize cell-free approaches for cardiac cell therapies. Numerous studies have indicated that paracrine mechanisms reasonably explain stem cell based heart repair. By imitating or adapting natural stem cells, as well as their secretions, and using them in conjunction with biocompatible materials, we can simulate the function of natural stem cells while avoiding the complications association with the first and second generation therapeutic options. Additionally, we can develop approaches to capture endogenous stem cells and directly transport them to the infarct site. Using these third generation therapeutic strategies, we can provide unprecedented opportunities for cardiac cell therapies. We hope that our designs will promote the use of chemical engineering approaches to transform, transport, and fabricate cell-free systems as novel cardiac cell therapeutic agents for clinical applications.}, number={6}, journal={ACCOUNTS OF CHEMICAL RESEARCH}, author={Li, Zhenhua and Hu, Shiqi and Cheng, Ke}, year={2019}, month={Jun}, pages={1687–1696} }
 @article{liu_hu_yang_li_huang_su_wang_cheng_2019, title={Hyaluronic Acid Hydrogel Integrated with Mesenchymal Stem Cell-Secretome to Treat Endometrial Injury in a Rat Model of Asherman's Syndrome}, volume={8}, ISSN={["2192-2659"]}, DOI={10.1002/adhm.201900411}, abstractNote={AbstractStem cell therapies have made strides toward the efficacious treatment of injured endometrium and the prevention of intrauterine adhesions, or Asherman's syndrome (AS). Despite this progress, they are limited by their risk of tumor formation, low engraftment rates, as well as storage and transportation logistics. While attempts have been made to curb these issues, there remains a need for simple and effective solutions. A growing body of evidence supports the theory that delivering media, conditioned with mesenchymal stem cells, might be a promising alternative to live cell therapy. Mesenchymal stem cell‐secretome (MSC‐Sec) has a superior safety profile and can be stored without losing its regenerative properties. It is versatile enough to be added to a number of delivery vehicles that improve engraftment and control the release of the therapeutic. Thus, it holds great potential for the treatment of AS. Here, a new strategy for loading crosslinked hyaluronic acid gel (HA gel) with MSC‐Sec is reported. The HA gel/MSC‐Sec treatment paradigm creates a sustained release system that repairs endometrial injury in rats and promotes viable pregnancy.}, number={14}, journal={ADVANCED HEALTHCARE MATERIALS}, author={Liu, Feiran and Hu, Shiqi and Yang, Hua and Li, Zhenhua and Huang, Ke and Su, Teng and Wang, Shaowei and Cheng, Ke}, year={2019}, month={Jul} }
 @article{hu_li_cores_huang_su_dinh_cheng_2019, title={Needle-Free Injection of Exosomes Derived from Human Dermal Fibroblast Spheroids Ameliorates Skin Photoaging}, volume={13}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.9b04384}, abstractNote={Human dermal fibroblasts (HDFs), the main cell population of the dermis, gradually lose their ability to produce collagen and renew intercellular matrix with aging. One clinical application for the autologous trans-dermis injection of HDFs that has been approved by the Food and Drug Administration aims to refine facial contours and slow down skin aging. However, the autologous HDFs used vary in quality according to the state of patients and due to many passages they undergo during expansion. In this study, factors and exosomes derived from three-dimensional spheroids (3D HDF-XOs) and the monolayer culture of HDFs (2D HDF-XOs) were collected and compared. 3D HDF-XOs expressed a significantly higher level of tissue inhibitor of metalloproteinases-1 (TIMP-1) and differentially expressed miRNA cargos compared with 2D HDF-XOs. Next, the efficacy of 3D HDF-XOs in inducing collagen synthesis and antiaging was demonstrated in vitro and in a nude mouse photoaging model. A needle-free injector was used to administer exosome treatments. 3D HDF-XOs caused increased procollagen type I expression and a significant decrease in MMP-1 expression, mainly through the downregulation of tumor necrosis factor-alpha (TNF-α) and the upregulation of transforming growth factor beta (TGF-β). In addition, the 3D-HDF-XOs group showed a higher level of dermal collagen deposition than bone marrow mesenchymal stem cell-derived exosomes. These results indicate that exosomes from 3D cultured HDF spheroids have anti-skin-aging properties and the potential to prevent and treat cutaneous aging.}, number={10}, journal={ACS NANO}, author={Hu, Shiqi and Li, Zhenhua and Cores, Jhon and Huang, Ke and Su, Teng and Dinh, Phuong-Uyen and Cheng, Ke}, year={2019}, month={Oct}, pages={11273–11282} }
 @article{qiao_hu_liu_zhang_ma_huang_li_su_vandergrif_tang_et al._2019, title={microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential}, volume={129}, ISSN={["1558-8238"]}, url={https://doi.org/10.1172/JCI123135}, DOI={10.1172/JCI123135}, abstractNote={Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.}, number={6}, journal={JOURNAL OF CLINICAL INVESTIGATION}, publisher={American Society for Clinical Investigation}, author={Qiao, Li and Hu, Shiqi and Liu, Suyun and Zhang, Hui and Ma, Hong and Huang, Ke and Li, Zhenhua and Su, Teng and Vandergrif, Adam and Tang, Junnan and et al.}, year={2019}, month={Jun}, pages={2237–2250} }
 @article{gao_zheng_li_feng_yan_chen_guo_liu_yang_wang_et al._2018, title={Biomimetic O-2-Evolving metal-organic framework nanoplatform for highly efficient photodynamic therapy against hypoxic tumor}, volume={178}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2018.06.007}, abstractNote={Improving the supply of O2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O2-evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen (1O2) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O2 from UiO-66. Subsequently, the generated O2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors.}, journal={BIOMATERIALS}, author={Gao, Shutao and Zheng, Pengli and Li, Zhenhua and Feng, Xiaochen and Yan, Weixiao and Chen, Shizhu and Guo, Weisheng and Liu, Dandan and Yang, Xinjian and Wang, Shuxiang and et al.}, year={2018}, month={Sep}, pages={83–94} }
 @article{su_huang_ma_liang_dinh_chen_shen_allen_qiao_li_et al._2019, title={Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury}, volume={29}, ISSN={["1616-3028"]}, DOI={10.1002/adfm.201803567}, abstractNote={AbstractCardiovascular disease is the leading cause of mortality worldwide. While reperfusion therapy is vital for patient survival post‐heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post‐ischemic recovery. A platelet‐inspired nanocell (PINC) that incorporates both prostaglandin E2 (PGE2)‐modified platelet membrane and cardiac stromal cell‐secreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct‐homing ability of platelet membrane and the overexpression of PGE2 receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be achieved by PINC, which combines the paracrine mechanism of cell therapy with the PGE2/EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.}, number={4}, journal={ADVANCED FUNCTIONAL MATERIALS}, author={Su, Teng and Huang, Ke and Ma, Hong and Liang, Hongxia and Dinh, Phuong-Uyen and Chen, Justin and Shen, Deliang and Allen, Tyler A. and Qiao, Li and Li, Zhenhua and et al.}, year={2019}, month={Jan} }
 @misc{li_hu_cheng_2018, title={Platelets and their biomimetics for regenerative medicine and cancer therapies}, volume={6}, ISSN={["2050-7518"]}, DOI={10.1039/c8tb02301h}, abstractNote={In this review, we will focus on the recent progress made in the development of platelet and platelet-mimicking delivery systems for the treatment of diseases.}, number={45}, journal={JOURNAL OF MATERIALS CHEMISTRY B}, author={Li, Zhenhua and Hu, Shiqi and Cheng, Ke}, year={2018}, month={Dec}, pages={7354–7365} }
 @article{li_shen_hu_su_huang_liu_hou_cheng_2018, title={Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair}, volume={12}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.8b05892}, abstractNote={Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system.}, number={12}, journal={ACS NANO}, author={Li, Zhenhua and Shen, Deliang and Hu, Shiqi and Su, Teng and Huang, Ke and Liu, Feiran and Hou, Lei and Cheng, Ke}, year={2018}, month={Dec}, pages={12193–12200} }