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

Abstract

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.