Abstract
Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.
Highlights
The global outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has already caused more than 4.5 million deaths worldwide
Analysis by real-time PCR showed that viral RNA could be detected in the incubated A549 cell-derived MPs (A-MPs) samples but not the unincubated A-MP samples (Fig. 1c), suggesting that SARS-CoV-2 is bound by A-MPs
We found that AO-MPs carrying more angiotensin-converting enzyme 2 (ACE2) molecules could adsorb more SARS-CoV-2 (Fig. 1f and Supplementary Fig. 1e)
Summary
The global outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has already caused more than 4.5 million deaths worldwide. The use of AO-MP-bound SARS-CoV-2 to treat AMs markedly inhibited the viral load in the cells (Fig. 3a, b). In the AO-MP group, more viral particles entered the AMs within the first 10 min of the incubation period (Fig. 3c), suggesting that AOMPs can efficiently deliver SARS-CoV-2 into AMs but generate an inhibitory effect on viral replication in these cells.
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