Precise Molecular Engineering of Multi-Suborganelle Targeted NIR Type‑I AIE Photosensitizer and Design of Cell Membrane-Anchored Anti-Tumor Pyroptosis Vaccine

Abstract

Photodynamically induced cell immunogenic death has emerged as an effective antitumor strategy because of its capacity to stimulate anti-tumor immunity for eliminating primary tumors and metastases. Considering that the short-lived reactive oxygen species (ROS) and the anoxic tumor microenvironment restrict the efficacy of conventional photodynamic therapy (PDT), a molecular framework of near-infrared (NIR) type I aggregation-induced emission (AIE) photosensitivities with tunable sub-organelles (including cell membranes, mitochondria, lipid drops, lysosomes, and endoplasmic reticulum) targeting type I ROS in precisely regulated subcellular locations are designed. Subsequent studies have discovered that under 660 nm laser irradiation, the cell membrane-targeted TCF-Mem can effectively induce pyroptosis of cancer cells, fully enhancing anti-tumor immunity in vivo in a preventive tumor vaccine model. Additionally, in vivo anti-tumor type I PDT can eradicate the primary tumor and, more importantly, inhibit the growth of distant tumors through in vitro actions, thereby obtaining specific anti-tumor immunity. This study provides a novel framework for the rational design of photosensitive sub-organelles targeting NIR type I AIE and offers a new perspective for innovative PDT-based tumor therapy and immune enhancement strategies.