Abstract: This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. pubs.acs.org/ptsci Article Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19 Bapurao Surnar, Mohammad Z. Kamran, Anuj S. Shah, and Shanta Dhar* Cite This: ACS Pharmacol. Transl. Sci. 2020, 3, 1371−1380 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. ACCESS Metrics & More Read Online Article Recommendations sı Supporting Information * ABSTRACT: There is urgent therapeutic need for COVID-19, a disease for which there are currently no widely effective approved treatments and the emergency use authorized drugs do not result in significant and widespread patient improvement. The food and drug administration-approved drug ivermectin has long been shown to be both antihelmintic agent and a potent inhibitor of viruses such as Yellow Fever Virus. In this study, we highlight the potential of ivermectin packaged in an orally administrable nanoparticle that could serve as a vehicle to deliver a more potent therapeutic antiviral dose and demonstrate its efficacy to decrease expression of viral spike protein and its receptor angiotensin-converting enzyme 2 (ACE2), both of which are keys to lowering disease transmission rates. We also report that the targeted nanoparticle delivered ivermectin is able to inhibit the nuclear transport activities mediated through proteins such as importin α/β1 heterodimer as a possible mechanism of action. This study sheds light on ivermectin-loaded, orally administrable, biodegradable nanoparticles to be a potential treatment option for the novel coronavirus through a multilevel inhibition. As both ACE2 targeting and the presence of spike protein are features shared among this class of virus, this platform technology has the potential to serve as a therapeutic tool not only for COVID-19 but for other coronavirus strains as well. KEYWORDS: spike protein, severe acute respiratory syndrome virus, angiotensin-converting enzyme 2, RNA virus trials, one aims to use the “wonder drug” ivermectin (IVM)14 in combination with aspirin, dexamethasone, and enoxaparin (Table S2). This trial uses IVM via a single dose of 200 μg/kg and may pose issues of toxicity and accelerated clearance from the bloodstream resulting in low effective dose.15,16 In this article, we report an orally administrable IVM-loaded nanoparticle (NP) and its ability to lower the expression of the ACE2 receptor and the SARS-CoV-2 spike protein. We recently developed a therapeutic IVM-loaded NP to treat Zika virus infection in the blood.17 The developed IVM nanoformulation allows the therapeutic to be gradually released into the bloodstream, which maintains its level in the blood at approximately the minimum effective therapeutic dose while keeping it below the maximum tolerated dose. This NP was constructed using poly(lactide-co-glycolide)-b-poly(ethylene glycol)-maleimide (PLGA-b-PEG-Mal) polymer, and was tagged to an Fc immunoglobulin fragment to take advantage of FcRn-driven crossing of the gut epithelial barrier to reach the bloodstream (Figure 1A). Here, we adopted the T he COVID-19, a..