Enhancing Immune Responses through Modulation of Innate Cell Microenvironments in Lymph Nodes with Virus‐Mimetic Vaccines

Nanovaccines hold significant promise for the prevention and treatment of infectious diseases. However, the efficacy of many nanovaccines is often limited by inadequate stimulation of both innate and adaptive immune responses. Herein, we explore a rational vaccine strategy aimed at modulating innate cell microenvironments within lymph nodes (LNs) to enhance the generation of effective immune responses. Inspired by the structure and natural infection process of viruses, we developed a versatile antigen and adjuvant co‐delivery platform, termed virus‐mimetic vaccines (VMVs). Specifically, polyarginine‐tagged antigens were noncovalently assembled onto nucleic acid nanogels containing cytosine‐phosphate‐guanine oligodeoxynucleotide via a salt‐bridge zipper mechanism, which can activate Toll‐like receptor 9. Upon intramuscular immunization, VMVs effectively drained into the LNs, recruiting and activating multiple innate cells, including CD8+ dendritic cells (DCs), CD103+ DCs, macrophages, plasmacytoid DCs, and neutrophils. This activation modulates the innate cell microenvironments and relocates antigen‐presenting cells within LNs, optimizing adaptive immune responses. VMVs induced a robust antigen‐specific immune response, characterized by high levels of neutralizing antibodies, augmented memory T cell activity, and enhanced development of germinal center B cells. Together, our findings demonstrate that dynamic modulation of innate cell microenvironments by VMVs leads to optimized generation of both humoral and cellular immunity against infectious diseases.