Inhaled Virus-Mimicking Particles Elicit Dose-Dependent Immune Response against SARS-CoV-2 with Sex-Bias ACE2 Activity in Mice

There is an urgent need to develop antigen presentation platforms that can induce broadly systemic immunity against multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subvariants. Here, virus-mimicking particles (VMP) are functionalized with substantial receptor binding domain protrusions from Delta variant SARS-CoV-2 on particle surface, programmed by biotin-streptavidin interaction. The fabricated VMP reveal superior pulmonary biodistribution and retention for at least 1 day in C57BL/6 female mice after oropharyngeal aspiration exposure. VMP at higher dosage elicit a robust and broad systemic immune response against SARS-CoV-2 variants in K18 human angiotensin-converting enzyme 2 (ACE2) transgenic mice. Furthermore, ACE2 expression in males dramatically decreases after high-dose VMP inhalation, while that in females remains comparable to baseline, which might be the reason that females are less vulnerable to the adverse effects than males. Overall, VMP are a promising candidate for next-generation viral inhibitors and immune stimulating particles against current and future SARS-CoV-2 variants.