Subcutaneous administration of an endocrine-mimetic, slow-release protein material reduces the severity of SARS-CoV-2 infection

Abstract

Slow-antigen release vaccination systems aim to replicate the prolonged antigen exposure occurring during natural viral infections, which usually last for days or weeks. We have developed a Zn-assisted, self-organizing protein material at the microscale, inspired by the granular depots for protein hormones, that slowly disassembles into functional building block polypeptides under physiological conditions. This endocrine-like platform acts as a dynamic protein depot for prolonged protein release. Having been validated in oncology, regenerative medicine, and in antimicrobial peptide delivery, it also shows promise for immune stimulation. Here, we evaluate, for the first time, whether such artificial secretory granules incorporating the SARS-CoV-2 Spike Receptor Binding Domain (RBD) can elicit a protective immune response against viral challenge in golden Syrian hamsters. The antigen, formulated as secretory granules, was administered in varying doses via intranasal or subcutaneous routes. While the formulations did not prevent infection, they enhanced viral clearance and mitigated body weight loss, particularly with subcutaneous administration. These effects, through the subcutaneous route, were achieved even in the absence of an adjuvant. Additionally, the granules triggered both antigen-specific humoral immunity and antigen-independent immunomodulatory effects, potentially linked to their amyloid-like structure. These findings demonstrate the dual mechanism of this platform, activating both adaptive and innate immune pathways, and its potential as a versatile, adjuvant-free system for enhancing immune responses against infectious diseases.