@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{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{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.}, 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={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{popowski_juan abad_george_silkstone_belcher_chung_ghodsi_lutz_davenport_flanagan_et al._2022, title={Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung}, url={https://doi.org/10.1016/j.vesic.2022.100002}, DOI={10.1016/j.vesic.2022.100002}, abstractNote={Respiratory diseases are among the leading causes of morbidity and mortality worldwide, coupled with the ongoing coronavirus disease 2019 (COVID-19) pandemic. mRNA lipid nanoparticle (LNP) vaccines have been developed, but their intramuscular delivery limits pulmonary bioavailability. Inhalation of nanoparticle therapeutics offers localized drug delivery that minimizes off targeted adverse effects and has greater patient compliance. However, LNP platforms require extensive reformulation for inhaled delivery. Lung-derived extracellular vesicles (Lung-Exo) offer a biological nanoparticle alternative that is naturally optimized for mRNA translation and delivery to pulmonary cells. We compared the biodistribution of Lung-Exo against commercially standard biological extracellular vesicles (HEK-Exo) and LNPs (Lipo), where Lung-Exo exhibited superior mRNA and protein cargo distribution to and retention in the bronchioles and parenchyma following nebulization administration. This suggests that inhaled Lung-Exo can deliver mRNA and protein drugs with enhanced pulmonary bioavailability and therapeutic efficacy.}, journal={Extracellular Vesicle}, author={Popowski, Kristen D. and Juan Abad, Blanca López and George, Arianna and Silkstone, Dylan and Belcher, Elizabeth and Chung, Jaewook and Ghodsi, Asma and Lutz, Halle and Davenport, Jada and Flanagan, Mallory and et al.}, year={2022}, month={Dec} }
 @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{lutz_popowski_dinh_cheng_2021, title={Advanced Nanobiomedical Approaches to Combat Coronavirus Disease of 2019}, volume={1}, url={https://doi.org/10.1002/anbr.202000063}, DOI={10.1002/anbr.202000063}, abstractNote={New infectious diseases are making themselves known as the human population grows, expands into new regions, and becomes more dense, increasing contact with each other and animal populations. Ease of travel has also increased infectious disease transmission and has now culminated into a global pandemic. The emergence of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has already infected over 83.7 million people and caused over 1.8 million deaths. While there have been vaccine candidates produced and supportive care implemented, the world is impatiently waiting for a commercially approved vaccine and treatment for the coronavirus disease of 2019 (COVID-19). The different vaccine types investigated for the prevention of COVID-19 all have great promise but face safety obstacles that must be first addressed. Some vaccine candidates of key interest are whole inactivated viruses, adeno-associated viruses, virus-like particles, and lipid nanoparticles. This review examines nanobiomedical techniques for combatting COVID-19 in terms of vaccines and therapeutics.}, number={3}, journal={Advanced NanoBiomed Research}, publisher={Wiley}, author={Lutz, Halle and Popowski, Kristen D. and Dinh, Phuong-Uyen C. and Cheng, Ke}, year={2021}, month={Mar}, pages={2000063} }
 @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. In this paper the authors show that nanovesicles coated with lung spheroid cell membranes expressing angiotensin-converting enzyme 2 can bind the spike protein of SARS-CoV-2, neutralizing the virus and preventing lung cell infections in murine and non-human primate models. The nanodecoys could represent a potential therapeutic agent to treat 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{carter_popowski_cheng_greenbaum_ligler_moatti_2021, title={Enhancement of Bone Regeneration Through the Converse Piezoelectric Effect, A Novel Approach for Applying Mechanical Stimulation}, volume={9}, ISSN={["2576-3113"]}, url={https://doi.org/10.1089/bioe.2021.0019}, DOI={10.1089/bioe.2021.0019}, abstractNote={Serious bone injuries have devastating effects on the lives of patients including limiting working ability and high cost. Orthopedic implants can aid in healing injuries to an extent that exceeds the natural regenerative capabilities of bone to repair fractures or large bone defects. Autografts and allografts are the standard implants used, but disadvantages such as donor site complications, a limited quantity of transplantable bone, and high costs have led to an increased demand for synthetic bone graft substitutes. However, replicating the complex physiological properties of biological bone, much less recapitulating its complex tissue functions, is challenging. Extensive efforts to design biocompatible implants that mimic the natural healing processes in bone have led to the investigation of piezoelectric smart materials because the bone has natural piezoelectric properties. Piezoelectric materials facilitate bone regeneration either by accumulating electric charge in response to mechanical stress, which mimics bioelectric signals through the direct piezoelectric effect or by providing mechanical stimulation in response to electrical stimulation through the converse piezoelectric effect. Although both effects are beneficial, the converse piezoelectric effect can address bone atrophy from stress shielding and immobility by improving the mechanical response of a healing defect. Mechanical stimulation has a positive impact on bone regeneration by activating cellular pathways that increase bone formation and decrease bone resorption. This review will highlight the potential of the converse piezoelectric effect to enhance bone regeneration by discussing the activation of beneficial cellular pathways, the properties of piezoelectric biomaterials, and the potential for the more effective administration of the converse piezoelectric effect using wireless control.}, journal={BIOELECTRICITY}, publisher={Mary Ann Liebert Inc}, author={Carter, Amber and Popowski, Kristen and Cheng, Ke and Greenbaum, Alon and Ligler, Frances S. and Moatti, Adele}, year={2021}, month={Sep} }
 @misc{popowski_dinh_george_lutz_cheng_2021, title={Exosome therapeutics for COVID-19 and respiratory viruses}, volume={2}, ISSN={["2688-268X"]}, url={https://doi.org/10.1002/VIW.20200186}, DOI={10.1002/VIW.20200186}, abstractNote={Respiratory viral diseases are a leading cause of mortality in humans. They have proven to drive pandemic risk due to their complex transmission factors and viral evolution. However, the slow production of effective antiviral drugs and vaccines allows for outbreaks of these diseases, emphasizing a critical need for refined antiviral therapeutics. The delivery of exosomes, a naturally secreted extracellular vesicle, yields therapeutic effects for a variety of diseases, including viral infection. Exosomes and viruses utilize similar endosomal sorting pathways and mechanisms, providing exosomes with the potential to serve as a therapeutic that can target, bind, and suppress cellular uptake of various viruses including the novel severe acute respiratory syndrome coronavirus 2. Here, we review the relationship between exosomes and respiratory viruses, describe potential exosome therapeutics for viral infections, and summarize progress toward clinical translation for lung-derived exosome therapeutics.}, number={3}, journal={VIEW}, publisher={Wiley}, author={Popowski, Kristen D. and Dinh, Phuong-Uyen C. and George, Arianna and Lutz, Halle and Cheng, Ke}, year={2021}, month={Jun} }
 @article{stine_popowski_su_cheng_2020, title={Exosome and Biomimetic Nanoparticle Therapies for Cardiac Regenerative Medicine}, volume={15}, url={https://doi.org/10.2174/1574888X15666200309143924}, DOI={10.2174/1574888X15666200309143924}, abstractNote={Exosomes and biomimetic nanoparticles have great potential to develop into a wide-scale therapeutic platform within the regenerative medicine industry. Exosomes, a subgroup of EVs with diameter ranging from 30-100 nm, have recently gained attention as an innovative approach for the treatment of various diseases, including heart disease. Their beneficial factors and regenerative properties can be contrasted with various cell types. Various biomimetic nanoparticles have also emerged as a unique platform in regenerative medicine. Biomimetic nanoparticles are a drug delivery platform, which have the ability to contain both biological and fabricated components to improve therapeutic efficiency and targeting. The novelty of these platforms holds promise for future clinical translation upon further investigation. In order for both exosome therapeutics and biomimetic nanoparticles to translate into large-scale clinical treatment, numerous factors must first be considered and improved. Standardization of different protocols, from exosome isolation to storage conditions, must be optimized to ensure batches are pure. Standardization is also important to ensure no variability in this process across studies, thus making it easier to interpret data across different disease models and treatments. Expansion of clinical trials incorporating both biomimetic nanoparticles and exosomes will require a standardization of fabrication and isolation techniques, as well as stricter regulations to ensure reproducibility across various studies and disease models. This review will summarize current research on exosome therapeutics and the application of biomimetic nanoparticles in cardiac regenerative medicine, as well as applications for exosome expansion and delivery on a large clinical scale.}, number={8}, journal={Current Stem Cell Research & Therapy}, publisher={Bentham Science Publishers Ltd.}, author={Stine, Sydney J. and Popowski, Kristen D. and Su, Teng and Cheng, Ke}, year={2020}, month={Nov}, pages={674–684} }
 @misc{popowski_lutz_hu_george_dinh_cheng_2020, title={Exosome therapeutics for lung regenerative medicine}, volume={9}, ISSN={["2001-3078"]}, url={https://doi.org/10.1080/20013078.2020.1785161}, DOI={10.1080/20013078.2020.1785161}, abstractNote={Exosomes are 30 to 100 nm extracellular vesicles that are secreted by many cell types. Initially viewed as cellular garbage with no biological functions, exosomes are now recognized for their thera...}, number={1}, journal={JOURNAL OF EXTRACELLULAR VESICLES}, publisher={Wiley}, author={Popowski, Kristen and Lutz, Halle and Hu, Shiqi and George, Arianna and Dinh, Phuong-Uyen and Cheng, Ke}, year={2020}, month={Jan} }
 @article{dinh_paudel_brochu_popowski_gracieux_cores_huang_hensley_harrell_vandergriff_et al._2020, title={Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis}, volume={11}, ISSN={["2041-1723"]}, url={http://dx.doi.org/10.1038/s41467-020-14344-7}, DOI={10.1038/s41467-020-14344-7}, abstractNote={Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis.}, number={1}, journal={NATURE COMMUNICATIONS}, publisher={Springer Science and Business Media LLC}, author={Dinh, Phuong-Uyen C. and Paudel, Dipti and Brochu, Hayden and Popowski, Kristen D. and Gracieux, M. Cyndell and Cores, Jhon and Huang, Ke and Hensley, M. Taylor and Harrell, Erin and Vandergriff, Adam C. and et al.}, year={2020}, month={Feb} }