Heavy-atom-free aza-BODIPY dye with twisted molecular conformation as type I photosensitizer for phototheranostics.

The hypoxic tumor microenvironment fundamentally undermines the efficacy of conventional type II photodynamic therapy (PDT), necessitating oxygen-independent strategies for durable cancer treatment. Here, we present a heavy-atom-free aza-BODIPY dye, NBDPTO, rationally engineered with twisted molecular conformation as a type I photosensitizer for multimodal imaging-guided phototherapy. By incorporating methoxy-substituted triarylamine donors and molecular rotors at the 2,6-positions, NBDPTO achieved enhanced intramolecular charge transfer, strong NIR-II fluorescence, and efficient spin-orbit charge transfer intersystem crossing (SOCT-ISC) without heavy atoms. Upon co-assembly with amphiphilic F-127, water-dispersible NBDPTO nanoparticles (NPs) were obtained, exhibiting broad NIR absorption peaking at 823 nm, intense NIR-II fluorescence emission peaking at ∼1100 nm, and remarkable photothermal conversion efficiency of 45 %. Under 808 nm irradiation, NBDPTO NPs efficiently generated superoxide anion radicals (O2-•) via a type I pathway, maintaining reactive oxygen species (ROS) productivity under hypoxia. Meanwhile, their high NIR-II fluorescence and strong photoacoustic (PA) signals enabled precise dual-modal imaging. In vivo, NBDPTO NPs enabled accurate tumor localization and achieved complete tumor eradication through combinational type I PDT and PTT. This work introduces a new molecular design paradigm for heavy-atom-free aza-BODIPY dyes, demonstrating their promise for clinically translatable, hypoxia-adaptive cancer treatment.