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

Abstract

ABSTRACT 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 O 2 /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.