Self‐Assembled Virus‐Like Particle Vaccines via Fluorophilic Interactions Enable Infection Mimicry and Immune Protection

Abstract Influenza epidemics persistently threaten global health. Vaccines based on virus‐like particles (VLPs), which resemble the native conformation of viruses, have emerged as vaccine candidates. However, the production of VLPs via genetic engineering remains constrained by challenges such as low yields, high costs, and being time consuming. In this study, a novel VLP platform is developed that could mimic infection and confer influenza protection through fluorination‐driven self‐assembly. The VLPs closely mimick the key steps in viral infection including dendritic cell (DC) attachment and pH‐responsive endo‐lysosomal escape, which enhances DC maturation and antigen cross‐presentation. It is also observed that the VLPs migrate from the injection site to the draining lymph nodes efficiently. Immunization with VLPs triggers both Th1 and Th2 cellular responses, thereby inducing an improved CD8 + T cell response along with strong antigen‐specific antibody responses. In several infected mouse models, VLP vaccines ameliorate weight loss, lung virus titers, pulmonary pathologies, and confer full protection against H1N1, H6N2, H9N2, and mixed influenza viruses. Therefore, the results support the potential of VLPs as an effective influenza vaccine with improved immune potency against infection. A methodology to generate VLPs based on fluorophilic interactions, which can be a general approach for development of pathogenic VLPs, is reported.