An Intrinsically Therapeutic Mn/Se Supramolecular Hydrogel for Cancer Immunotherapy

ABSTRACT Current biomaterial‐assisted cancer immunotherapy predominantly relies on hydrogels as passive depots for the controlled release of encapsulated drugs or immune modulators. This paradigm, while effective, inherits the complexities of drug loading, stability, and release kinetics. Herein, we report an intrinsically therapeutic supramolecular material whose matrix‐forming components directly provide therapeutic functions without requiring separately loaded drugs or immune agonists. We engineer a peptide‐based hydrogel through the Mn 2+ ‐coordinated self‐assembly of a selenopeptide, FHAH . In this design, the selenated motif drives enhanced natural killer (NK) cell activation, while the coordinatively bound Mn 2+ acts as both a structural crosslinker and a potent activator of the cGAS‐STING pathway. This structurally integrated, multifunctional hydrogel directly induces immunogenic cell death in tumor cells and simultaneously activates both the STING and NK cell axes, orchestrating a concerted innate immune response. In vivo, localized application markedly suppresses primary tumors, inhibits distant tumor growth, and suppresses lung metastasis by remodeling the immunosuppressive microenvironment and eliciting systemic antitumor immune responses. This work moves beyond the conventional carrier paradigm to establish a new class of self‐therapeutic biomaterials in which therapeutic function is molecularly encoded into the material structure, offering a streamlined strategy for next‐generation cancer immunotherapy.