Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Abstract

SARS-CoV-2 can infect cells through endocytic uptake, a process which can be targeted by inhibition of lysosomal proteases. However, clinically this approach fared poorly with an oral regimen of hydroxychloroquine that was accompanied by significant toxicity due to off-target effects. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, 100-150 nm in diameter, and possess a negative surface charge which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2-WA1 and its Omicron variant in a human lung epithelium model. This study demonstrates that organelle-targeted delivery is an effective means to inhibit viral infection.

Role of lysosome in healing neurological disorders by nano-bioengineering

“…Ideally, this can be achieved by generating bioengineered super-functional lysosomes by nanoparticle-mediated direct delivery of activated lysosome-residing enzymes, including lysosomal acid-hydrolases (proteases-cathepsins/phosphatases/nucleases/glycosidases/peptidases/sulphatases/lipases), lysosomal-enzyme activators, metabolites, AAs, peptides, proteins, directly to the lysosomal compartments, which might have higher ability to dissolve cellular-lysosomal aggregates. As a treatment measure of Covid-19, inhibition of lysosomal luminal proteases by endocytic entry and subsequent lysosomal delivery of negatively surface-charged mefloquine loaded poly-(glycerol monostearate-co-ε-caprolactone) nanoparticles (MFQ-NPs) to lungs-cells, have been shown to mitigate SARS-CoV2 infection ( Petcherski et al, 2023 ). Identical nanoparticle-mediated intervention can be applied to alter lysosomal-activity in the context of neurodegeneration.…”

Strategies for the development and approval of COVID-19 vaccines and therapeutics in the post-pandemic period

“…[134][135][136] Nanomaterials can be engineered to target specific cells, reducing drug toxicity. 137 Some nanozymes exhibit favorable biological distribution and can inhibit virus infection without harming host cells, thereby optimizing therapeutic outcomes and reducing drug side effects. 138,139 Finally, aiming for convenient treatment, future therapeutic drugs will likely focus on oral administration.…”