Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.

Remote control of stem cell differentiation in vivo by stimuli-responsive nanomaterials with the use of tissue-penetrative stimuli is an appealing strategy for versatile regulation in stem cell therapy. In this study, an upconversion nanotransducer (UCNT)-based nanocomplex with photolabile caging of chondro-inductive kartogenin (KGN) and/or either calcium chelator or calcium supplier (caged calcium), and subsequent coupling of integrin-binding ligand via cyclodextrin-adamantine supramolecular complexation is utilized. Nearinfrared (NIR)-to-ultraviolet light conversion by UCNT nanocomplex triggered intracellular photo-uncaging and release of cargo molecules, thereby allowing direct regulation of real-time intracellular calcium levels. While intracellular KGN delivery led to the differentiation of human mesenchymal stem cells (hMSCs) into hypertrophic chondrocytes, NIR-regulated intracellular calcium decrease and KGN delivery induced their differentiation into chondrocytes by inhibiting hypertrophy. Conversely, intracellular calcium increase and KGN delivery promoted the differentiation of hMSCs into osteoblasts via endochondral pathway. To the best of knowledge, this is the first demonstration of utilizing NIR-controllable nanomaterials for regulating stem cell differentiation by controlling intracellular calcium, both in vitro and in vivo. This versatile control can facilitate the translation of stem cells to remotely controlled treatment of diseases in composite tissues involving various cell types.

Cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C, 1) suffers from low oral bioavailability due to low intestinal membrane permeability and poor metabolic stability, and intravenous infusion is usually adopted as the clinical standard dosing administration. To develop an oral alternative for 1 and utilize the intestinal oligopeptide transporter 1 (PepT1), a series of 5'-amino acid ester derivatives of 1 was synthesized to clarify which modification was the most suitable to increase the oral bioavailability of 1. Their apical-to-basolateral permeability across Caco-2 cells and the antiproliferative activity with HL-60 cells were screened. 5'-Valyl prodrug 2 demonstrated the highest permeability and was selected for further study. Glycylsarcosine (gly-sar, a typical substrate of PepT1) uptake by Caco-2 cells can be inhibited by 2 in a concentration-dependent manner, and IC(50) for 2 was 2.18 +/- 0.12 mM. The uptake of 2 was markedly increased in the long-term leptin-treated Caco-2 cells compared with the control Caco-2 cells, and was significantly inhibited by the excess of gly-sar, but not by l-valine. A dose-proportional pharmacokinetics was observed in rats when 5, 15, 30 mg/kg doses of 2 (calculated as 1) were orally administered. The oral absolute bioavailability of 1 was 60.0% and 21.8% after 2 and 1 were orally administered to rats 30 mg/kg, respectively. Following oral administration of 15 mg/kg, the absorption and bioactivation of 2 were extensive and rapid, over 98% of prodrug hydrolysis occurring before appearance in the portal vein. The in vivo dispositions of 1-beta-D-arabinofuranosyluracil (ara-U), a deaminated product of 1, were investigated. Oral administration of 2 resulted in an increased 1/ara-U ratio (2.76) in the blood, much higher than that (1.25) after 1 orally taken. Overall, these results demonstrated that the PepT1-mediated absorption of 2 and the increased metabolic stability resulted in a dramatic increase in the oral bioavailability of 1 in rats and further corroborated the thought that prodrug design strategy targeting intestinal PepT1 was an important and promising strategy to improve oral bioavailability of poorly absorbed drugs.