Mitochondria-targeted D-π-A near-infrared photosensitizer with synchronous type-I/type-II ROS generation for hypoxia-tolerant photodynamic tumor therapy

Photodynamic therapy (PDT) holds great promise for tumor treatment, but its clinical translation is greatly hindered by the drawbacks of conventional photosensitizers (PSs), such as insufficient reactive oxygen species (ROS) generation, exclusive type‑II photoreaction, poor subcellular targeting, and compromised efficacy in hypoxic tumors. Herein, we rationally designed and synthesized a mitochondria‑targeted near‑infrared (NIR) photosensitizer Mito‑IsTp with a classic D-π-A architecture, using isophorone as the electron acceptor, methoxy‑modified triphenylamine as the electron donor, benzene as the π‑bridge, and triphenylphosphonium as the mitochondrial‑targeting group. Mito‑IsTp displays a maximum emission peak at 770 nm within the NIR‑I window, together with satisfactory photostability and solvent‑dependent optical performance. Upon 660 nm NIR light irradiation, Mito‑IsTp can simultaneously produce type‑I (•OH, O 2 -• ) and type‑II ( 1 O 2 ) ROS with much higher efficiency than commercial Rose Bengal and Chlorin e6 (Ce6). Confocal imaging verifies its excellent mitochondrial targeting ability in HeLa cells with a Pearson correlation coefficient of 0.97. In vitro experiments reveal negligible dark toxicity and efficient phototoxicity to induce cancer cell apoptosis through ROS-mediated mitochondrial damage. In vivo studies on HeLa tumor‑bearing nude mice further show that Mito‑IsTp ‑mediated PDT significantly suppresses tumor growth without obvious systemic toxicity or organ injury, confirmed by body weight recording, H&E staining, blood routine tests, and hemocompatibility assessment. This work presents a high‑performance NIR PS with dual‑pathway ROS generation and precise mitochondrial targeting, establishing a feasible paradigm for hypoxia‑resistant and mitochondria‑targeted tumor PDT.