Light-Activatable Nitric Oxide Release via Intramolecular Electron Transfer for Tumor Pyroptosis Induction.

Developing long-wavelength-activated nitric oxide (NO) donors has attracted increasing attention for achieving precise photo-controlled NO release with deep tissue penetration and minimal phototoxicity, yet this remains a major challenge. Herein, we report a deep-red light-triggered NO-releasing molecule (DBTBT-NO) via a novel photoexcitation-mediated electron transfer process to induce abundant peroxynitrite generation. The DBTBT-NO can be activated by deep-red light to release NO, which is facilitated by photoinduced intramolecular charge separation. Meanwhile, superoxide anions generated during photolysis rapidly react with NO to produce massive peroxynitrite in mitochondria, which induces tumor cell pyroptosis at a low light dose of 15 J/cm2 and a low concentration of 0.4 µm. The robust pyroptosis triggered by DBTBT-NO effectively inhibits tumor growth and metastasis in mice with excellent biosafety. This is the first report on boosting peroxynitrite generation through long-wavelength photolysis of benzisothiadiazole-based N-nitrosanilines via a distinct mechanism. This work provides a new approach to fabricate unimolecular peroxynitrite photoinitiators with high pyroptosis induction efficiency, facilitating simplified and improved photoimmunotherapy.