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.