Universal STING Pathway-Activating Complexes Counteract Viral Immune Evasion and Boost Antiviral Responses.

Abstract

Viruses have evolved multiple mechanisms to counteract the stimulator of the interferon genes (STING) pathway, resulting in the suppression of antiviral responses. Accordingly, in addition to developing STING agonist analogs with enhanced stability and deliverability, overcoming the defective STING function in virus-infected cells is essential for defense against viral infections. In this study, we developed STING pathway-activating complexes (SPAC) based on bioinspired vesicles that display and multimerize STING molecules with a specific affinity for agonist binding. As a broad-spectrum antiviral agent, this universal STING mimic triggers IFN-I signaling independently of endogenous STING. In infectious models, including CMV and SARS-CoV-2 infection, both prophylactic and therapeutic regimens of SPAC can reduce viral load and disease severity. These results indicate that SPAC, functioning as a host-targeted immune modulator, provides the distinct advantage of broad-spectrum therapy against infectious diseases caused by both DNA and RNA viruses, particularly those with strong STING antagonistic functions. The endogenous STING-independent activation mechanisms of SPAC may provide a universal therapy for infectious diseases, potentially serving as a candidate option to defend against future pandemics of "Disease X".