Pursuing precise cancer therapy: tumor microenvironment-triggered hydrogen bond self-assembly enables photoreaction transition from type II to type I

Controllable photoreaction transition of photosensitizers (PSs) provides a highly promising approach for achieving efficient photodynamic therapy (PDT). However, tumor microenvironment-triggered phototransition remains a significant challenge and has not yet been reported. In this work, we develop a hydrogen bond self-assembly (HBSA) strategy that is triggered by the acidic tumor microenvironment to enable the photodynamic transition of tetra(4-carboxylphenyl)porphyrin (TCPP) PSs from type II to type I reactions. Upon self-assembly of TCPP monomers into TCPP assemblies (TCPP-ass), the generated reactive oxygen species shift from singlet oxygen to superoxide anions, which induces caspase-3/GSDME-mediated programmed pyroptosis, enabling rapid and complete solid tumor elimination with minimized adverse effects and enhanced therapeutic efficacy. Crucially, the HBSA process occurs exclusively within tumor cells, and this tumor-specific self-assembly strategy not only utilizes high tissue penetration of TCPP molecular-PSs, but also avoids phototoxicity caused by the formation and accumulation of TCPP-ass nano-PSs in normal tissue, providing an innovative approach for precise cancer therapy.