Adaptive Protein Corona Nanoassemblies Couple Cytokine Signaling with Endogenous Antigen Transport for Systemic Cancer Immunity

Protein corona formation is widely viewed as an inevitable but poorly controlled event when nanoparticles encounter biological environments. Converting this interfacial layer into a programmable functional entityremains a major challenge. Here, we report an adaptive protein corona nanoassembly strategy that integrates cytokine signaling with endogenous antigen transport. Coordination-engineered manganese nanoscaffolds were assembled with interleukin-12 (IL-12) and protected by an enzyme-responsive hyaluronic acid shell to form nanoshuttles (NSs) capable of dynamic protein recruitment in the tumor microenvironment (TME). Following enzymatic activation, exposure of the cationic manganese surface promotes adaptive corona formation and efficient capture of tumor-derived antigens. The resulting antigen-associated nanoassemblies traffic to tumor-draining lymph nodes, where they facilitate dendritic cell cross-presentation and tumor-specific T-cell priming. This coordinated process couples intratumoral cytokine signaling with antigen delivery, generating potent systemic antitumor immunity at significantly reduced IL-12 doses. These findings establish adaptive protein corona nanoassembly as a chemical strategy for programming nano-bio interfaces to coordinate cytokine signaling and antigen transport.