Spatiotemporal Dynamic Immunomodulation by Infection‐Mimicking Gels Enhances Broad and Durable Protective Immunity Against Heterologous Viruses

Abstract Despite their safety and widespread use, conventional protein antigen‐based subunit vaccines face significant challenges such as low immunogenicity, insufficient long‐term immunity, poor CD8⁺ T‐cell activation, and poor adaptation to viral variants. To address these issues, an infection‐mimicking gel (IM‐Gel) is developed that is designed to emulate the spatiotemporal dynamics of immune stimulation in acute viral infections through in situ supramolecular self‐assembly of nanoparticulate‐TLR7/8a (NP‐TLR7/8a) and an antigen with tannic acid (TA). Through collagen‐binding properties of TA, the IM‐Gel enables sustained delivery and enhanced retention of NP‐TLR7/8a and protein antigen in the lymph node subcapsular sinus of mice for over 7 days, prolonging the exposure of vaccine components in both B cell and T cell zones, leading to robust humoral and cellular responses. The IM‐Gel system with the influenza A antigen confers cross‐protection against multiple influenza subtypes (H1N1, H5N2, H3N2, H7N3, and H9N2) with long‐term immune responses. Combination of the IM‐Gel with the SARS‐CoV‐2 spike protein also elicits strong cross‐reactive antibody responses against multiple SARS‐CoV‐2 variants (Alpha, Beta, NY510+D614G, Gamma, Kappa, and Delta). The IM‐Gel, as a programmable immunomodulatory material, provides a vaccine design principle for the development of next‐generation universal vaccines that can elicit broad and durable protective immunity against emerging viruses.