Mannose Glycation of Tumor‐Associated Antigens via Intratumoral Maillard Reaction Mediated by a Photothermal Nano‐Catalyst for Enhanced Antigen‐Presenting Cell Targeting

ABSTRACT

Immunogenic cell death (ICD) represents a classical pathway for generating personalized anticancer vaccines in situ. However, the poor immunogenicity of released tumor‐associated protein antigens (TAAs) remains a major limitation to their therapeutic efficacy. Herein, we developed mannose‐loaded hollow polydopamine nanoparticles (Man@HDA‐Pd) and proposed intratumoral‐Maillard reaction as a new strategy for the glycation of TAAs. The local administration of as‐prepared Man@HDA‐Pd could efficiently induce ICD effects, leading to the release of abundant TAAs. Furthermore, leveraging the photothermal effect, catalase‐like properties of Man@HDA‐Pd, these released TAAs undergo mannose‐directed glycation via the Maillard reaction, further generating advanced glycation end products (AGEs)‐like antigens (denoted as Man‐TAAs), thereby endowing them with dendritic cell (DC)‐targeting ability and significantly improving their internalization. Concurrently, this man‐mediated glycation process is accompanied by elevated reactive oxygen species (ROS), suppressed cell proliferation, and exhibited characteristics of cellular senescence within tumor cells. Additionally, the delivery of Man@HDA‐Pd competitively displaces glycans on the immunosuppressive glycoprotein PD‐L1 on tumor cell surfaces via a sugar‐replacement effect, which would impair its function and inhibit tumor immune escape. Taken together, this work proposes and validates an in situ Maillard‐based glycation strategy for enhanced immunotherapy, providing valuable insights for the design of in situ tumor vaccines.