@article{wang_hu_popowski_liu_zhu_mei_li_hu_dinh_wang_et al._2024, title={Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2}, volume={15}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-024-45628-x}, number={1}, journal={NATURE COMMUNICATIONS}, author={Wang, Zhenzhen and Hu, Shiqi and Popowski, Kristen D. and Liu, Shuo and Zhu, Dashuai and Mei, Xuan and Li, Junlang and Hu, Yilan and Dinh, Phuong-Uyen C. and Wang, Xiaojie and et al.}, year={2024}, month={Mar} }
 @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. A bioadhesive hydrogel delivered via inhalation efficiently coats the airway and restricts SARS-CoV-2 virus variant penetration in mice and non-human primates}, 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{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={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{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={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.}, 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{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} }
 @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{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} }
 @misc{mei_cheng_2020, title={Recent Development in Therapeutic Cardiac Patches}, volume={7}, ISSN={["2297-055X"]}, DOI={10.3389/fcvm.2020.610364}, abstractNote={For the past decades, heart diseases remain the leading cause of death worldwide. In the adult mammalian heart, damaged cardiomyocytes will be replaced by non-contractile fibrotic scar tissues due to the poor regenerative ability of heart, causing heart failure subsequently. The development of tissue engineering has launched a new medical innovation for heart regeneration. As one of the most outstanding technology, cardiac patches hold the potential to restore cardiac function clinically. Consisted of two components: therapeutic ingredients and substrate scaffolds, the fabrication of cardiac patches requires both advanced bioactive molecules and biomaterials. In this review, we will present the most state-of-the-art cardiac patches and analysis their compositional details. The therapeutic ingredients will be discussed from cell sources to bioactive molecules. In the meanwhile, the recent advances to obtain scaffold biomaterials will be highlighted, including synthetic and natural materials. Also, we have focused on the challenges and potential strategies to fabricate clinically applicable cardiac patches.}, journal={FRONTIERS IN CARDIOVASCULAR MEDICINE}, author={Mei, Xuan and Cheng, Ke}, year={2020}, month={Nov} }