Cationic Engineering of Photosensitizers Drives Mitochondrial Targeting and Enhanced ROS-Based Tumor Phototherapy

Photodynamic therapy (PDT) is a promising anticancer strategy but remains limited by inefficient reactive oxygen species (ROS) generation and insufficient subcellular targeting. Here, we report a cationic engineering strategy to enhance mitochondrial targeting and ROS-amplified photodynamic tumor therapy. A neutral aggregation-induced emission (AIE) photosensitizer (PS) was stepwise converted into monocationic (PS-Bu) and dicationic (PS–PPh) derivatives, enabling precise regulation of molecular charge density. Cationic modification modulates excited-state energetics, promotes intersystem crossing, and simultaneously enhances Type I and Type II ROS generation under visible-light irradiation. The increased positive charge drives preferential mitochondrial accumulation, leading to pronounced mitochondrial membrane depolarization, intracellular ROS amplification, cell-cycle arrest, and apoptosis. Consequently, PS–PPh exhibits markedly enhanced phototoxicity toward HepG2 cells while maintaining negligible dark toxicity. In vivo, PS–PPh achieves superior tumor growth suppression in HepG2 xenograft models, accompanied by reduced proliferation, enhanced apoptosis, and alleviation of tumor hypoxia, without detectable systemic toxicity. This work establishes cationic modulation as an effective molecular design paradigm for mitochondria-targeted and ROS-enhanced photodynamic cancer therapy.