HACE2-Exosome-Based Nano-Bait for Concurrent SARS-CoV-2 Trapping and Antioxidant Therapy.

Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seriously threatening human health. Following SARS-CoV-2 infection, immune cell infiltration creates an inflammatory and oxidative microenvironment, which can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death. Clinically, a safe and effective treatment strategy remains to be established. Herein, a nano-bait strategy for inhibition of SARS-CoV-2 infection by redirecting viral attack while simultaneously relieving inflammation is developed. Specifically, the nano-bait was based on the exosome-sheathed polydopamine (PDA@Exosome) nanoparticles, which were generated by exocytosis of the PDA nanoparticles from H293T cells. In this approach, PDA@Exosome inherits from the source cells of H293T cells a surface display of ACE2 through pre-engineered expression. The resulting PDA@Exosome can compete with ACE2-expressing epithelial cells for S protein binding, in either the pre-exposure or post-exposure route. Moreover, relying on the ability of PDA to intercept and deactivate radical species, the PDA@Exosome can significantly attenuate the level of inflammatory cytokines by mediating oxidative stress, a major cause of organ injury. Due to its high trapping, multiple antioxidant ability, and good biocompatibility, the HACE2-exosome based nano-bait is a promising robust antiviral nanotherapeutics for the ongoing COVID-19 pandemic.

A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases.

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID-19 targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-cytotoxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID-19 complications, and other related diseases. IMPORTANCE With the Delta variant currently fueling a resurgence of new infections in the fully vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanisms of action that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations, and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. Further development of the compound will provide an important tool in the fight against COVID-19 and its complications, as well as future outbreaks of new viruses.