An Activatable and Covalent Tumor-Associated Antigen Capturer Enabling Systemic Injection In Vivo for Promoted Antitumor Immunity

Antigen-capturing nanomaterials hold great promise for cancer immunotherapy; however, the need for tumor localized administration and limited antigen-binding affinity remains the “Achilles heel” of this strategy. Herein, we present a tumor microenvironment (TME)-activatable nanoplatform, TDR848@FPB, designed for systemic administration and enhanced covalent capture of tumor-associated antigens (TAAs), enabling effective immunotherapy with minimal off-target effects and independent of localized tumor administration. This platform encapsulates a photosensitizer-conjugated, light-activated toll-like receptor (TLR) agonist, which induces immunogenic cell death and triggers a pro-inflammatory TME conducive to antigen capture upon light irradiation. TDR848@FPB covalently binds TAA-generated postphotodynamic therapy and promotes their efficient delivery to enhance dendritic cell maturation, T cell activation, and immunogenetic reprogramming of the TME. Following intravenous injection and light irradiation, TDR848@FPB demonstrates superior 1O2 generation capability and TAA capture efficiency, leading to significant tumor growth inhibition. Moreover, the captured TAAs and TLR agonists synergistically activate adaptive antitumor immunity, as evidenced by their potentiated T cell responses. These findings highlight the critical role of TME-activatable covalent antigen capture in enabling systemic delivery of antigen-capturing nanomaterials and validate TDR848@FPB as a versatile platform for precise cancer immunotherapy with a high therapeutic outcome and low off-target effects, independent of tumor localized administration.