Oxygen-Regenerative NIR Aza-BODIPY Photosensitizers for Hypoxia-Tolerant Photodynamic Therapy

Near-infrared (NIR) photosensitizers (PSs) capable of producing cytotoxic reactive oxygen species (ROS) via oxygen-engaged electron- and energy-transfer pathways under excitation beyond 800 nm are highly attractive for deep-tissue photodynamic therapy (PDT). However, their ROS generation is fundamentally limited by the low photon energy of long-wavelength excitation and the hypoxic tumor microenvironment. Herein, we report three oxygen-regenerative NIR aza-BODIPY PSs for efficient hypoxia-tolerant PDT under 808 nm excitation. Mechanistic studies identify PS radical-ion pairs as the key intermediates that couple water oxidation-driven in situ O₂/proton (H⁺) generation with downstream oxygen reduction to enable efficient hypoxia-tolerant •OH production. In parallel, efficient H⁺ generation and strong H⁺ affinity of the target PS (NJ853) promote H⁺-engaged oxygen photoreduction, affording a ∼56-fold enhancement in •OH generation compared with commercial PS indocyanine green (ICG). This hypoxia-tolerant intracellular ROS generation enables NJ853@NPs to induce apoptosis-dominant cancer cell killing and superior in vivo PDT efficacy under 808 nm irradiation. This work establishes an oxygen-regenerative photoredox pathway for NIR PSs, opening a new avenue to overcome the longstanding hypoxia limitation in deep-tissue PDT.