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

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: H₂O₂-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 H₂O₂ 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.