Self‐Immolative Activatable Nanoassembly toward Immuno‐Photodynamic Therapy in TME

Abstract Conventional “always‐on” photosensitizers are often plagued by off‐target toxicity and poor tumor selectivity, limiting the clinical efficacy of photodynamic therapy (PDT). Herein, an innovative quinone methide (QM)‐gated self‐immolative ‘OFF‐ON’ nano‐photosensitizer platform ( Pyz/PS ) is reported for highly efficient immuno‐photodynamic therapy. Unlike previous approaches, this study unprecedentedly introduces a self‐immolative nanoassembly platform integrating a rationally designed amphiphilic receptor (Pyz) with commercially available PSs (TPPS, Eosin Y, or Rose Bengal). The Pyz molecule is meticulously engineered with four functional motifs: H 2 O 2 ‐responsive boronate ester trigger, QM‐based self‐immolative linker, pyridinium/amide groups for anion recognition, and a hydrophobic hexadecyl tail for aqueous self‐assembly. In aqueous solution, Pyz/PS forms nano‐photosensitizers that suppress the fluorescence and ROS generation of the PS through PET. In response to elevated H 2 O 2 levels in TME, the nanoassemblies undergo selective disintegration, reinstating PS activity for spatially confined, imaging‐guided PDT. Concomitantly, the liberated QM species deplete intracellular GSH, amplifying the oxidative stress and further boosting PDT efficacy. Comprehensive in vitro and in vivo studies demonstrate that the Pyz/TPPS nanoplatform not only suppresses tumor growth but also triggers potent antitumor immune responses. This study presents an unprecedented and translationally promising strategy for activatable nano‐photosensitizers, advancing the frontier of PDT‐based cancer immunotherapy.