Lysosome‐Targeted D–π–A Near‐Infrared Photosensitizer With Dual Type‐I/Type‐II ROS Generation for Hypoxia‐Resilient Photodynamic Tumor Therapy

ABSTRACT Photodynamic therapy (PDT) is a promising minimally invasive antitumor approach, but its clinical efficacy is severely limited by the single Type‑II reaction of conventional photosensitizers (PSs), insufficient subcellular targeting and poor performance in hypoxic tumors. Herein, a lysosome‑targeted D‑‐π‐‑A near‑infrared PS Lyso‑IsTp was designed and synthesized, with isophorone as acceptor, methoxy‑modified triphenylamine as donor, benzene as π‑bridge and 4‑(2‑chloroethyl)morpholine as targeting moiety. It emitted fluorescence at 750 nm with good photostability and solvent‑dependent properties. Under 660 nm irradiation, Lyso‑IsTp simultaneously produced Type‑I (•OH, O 2 −• ) and Type‐II ( 1 O 2 ) ROS. Confocal imaging confirmed its excellent lysosome targeting in HeLa cells with a Pearson coefficient of 0.97. It showed negligible dark toxicity and remarkable phototoxicity, inducing apoptosis via ROS‑mediated lysosomal damage. In vivo studies on tumor‑bearing nude mice revealed that Lyso‑IsTp ‑mediated PDT significantly inhibited tumor growth with obvious necrosis. Biosafety tests including body weight, H&E staining, and blood analysis demonstrated no obvious systemic toxicity or organ damage. This work provides a high‑performance lysosome‑targeted NIR PS with dual ROS generation, offering a feasible strategy for hypoxia‑tolerant and organelle‑specific antitumor PDT.