The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.

PTEN is a well-characterized tumour-suppressor gene that is lost or mutated in about half of metastatic castration-resistant prostate cancers and in many other human cancers. The restoration of functional PTEN as a treatment for prostate cancer has however proven difficult. Here, we show that PTEN mRNA can be reintroduced into PTEN-null prostate cancer cells in vitro and in vivo via its encapsulation in polymer-lipid hybrid nanoparticles coated with a poly(ethylene glycol) shell. The nanoparticles are stable in serum, elicit low toxicity, enable high PTEN mRNA transfection in prostate cancer cells, and lead to significant inhibition of tumour growth when delivered systemically in multiple mouse models of prostate cancer. We also show that the restoration of PTEN function in PTEN-null prostate cancer cells inhibits the PI3K-AKT pathway and enhances apoptosis. Our findings provide proof-of-principle evidence of the restoration of mRNA-based tumour suppression in vivo .

Breast cancer develops from local tissue but is characterized by a distinct metastatic pattern involving regional lymph nodes and distant organs, which is the primary cause of high mortality in breast cancer patients. Herein, optimal docking nanoparticles (NPs) composed of a laurate-functionalized Pt­(IV) prodrug (Pt­(lau)), human serum albumin (HSA), and lecithin were predicted by computational modeling, prepared by nanoprecipitation, and validated by fluorescence spectroscopy. As macrophages have been reported to be preferentially recruited by breast cancer, Rex, the exosome spontaneously secreted by murine RAW 264.7 cells, was isolated to encapsulate the NPs. This high-performance delivery system, called NPs/Rex, possessed the desired physicochemical properties, enhanced colloidal stability, and redox-triggered release profile. Investigations of cytodynamics proved that NPs/Rex was internalized through multiple pathways, avoided entrapment by bilayers, and successfully platinized nucleic acids after bioreduction in the cytosol. Intracellular activation of Pt­(lau) was confirmed by observing the characteristic effects of cisplatin on cell proliferation and the cell cycle following treatment with NPs/Rex. During in vivo application, the bioinspired Rex coating endowed docking NPs with prolonged blood circulation, smart organ tropism, and enhanced biocompatibility, as well as robust platinum (Pt) chemotherapy for breast cancer cells in orthotopic tumors of fat pads and metastatic nodules of lungs. Therefore, this favorable nanoplatform might provide valuable insight into the derivatization and development of Pt anticancer drugs used currently in the clinic.

Many patients infected with coronaviruses, such as SARS-CoV-2 and NL63 that use ACE2 receptors to infect cells, exhibit gastrointestinal symptoms and viral proteins are found in the human gastrointestinal tract, yet little is known about the inflammatory and pathological effects of coronavirus infection on the human intestine. Here, we used a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by patient organoid-derived intestinal epithelium interfaced with human vascular endothelium to study host cellular and inflammatory responses to infection with NL63 coronavirus. These organoid-derived intestinal epithelial cells dramatically increased their ACE2 protein levels when cultured under flow in the presence of peristalsis-like mechanical deformations in the Intestine Chips compared to when cultured statically as organoids or in Transwell inserts. Infection of the intestinal epithelium with NL63 on-chip led to inflammation of the endothelium as demonstrated by loss of barrier function, increased cytokine production, and recruitment of circulating peripheral blood mononuclear cells (PBMCs). Treatment of NL63 infected chips with the approved protease inhibitor drug, nafamostat, inhibited viral entry and resulted in a reduction in both viral load and cytokine secretion, whereas remdesivir, one of the few drugs approved for COVID19 patients, was not found to be effective and it also was toxic to the endothelium. This model of intestinal infection was also used to test the effects of other drugs that have been proposed for potential repurposing against SARS-CoV-2. Taken together, these data suggest that the human Intestine Chip might be useful as a human preclinical model for studying coronavirus related pathology as well as for testing of potential anti-viral or anti-inflammatory therapeutics.