Functional Design of Near‐Infrared Aggregation‐Induced Emission Photosensitizers Targeting Cell Membrane and Mitochondria Enhance Photodynamic Efficiency

ABSTRACT Photodynamic therapy (PDT) efficacy is constrained by the short lifespan and restricted diffusion of ROS, preventing them from reaching key targets. Recent studies shows that dual‐organelle‐targeting photosensitizers can enhance tumor inhibition by improving ROS utilization. In this study, we regulated the electron acceptor to design and synthesize two near‐infrared aggregation‐induced emission (AIE) photosensitizers, TTP‐B and TTP‐M , capable of dual targeting of both the cell membrane and mitochondria. By adjusting molecular charge and conformation, these photosensitizers displayed strong AIE, generated type I and II ROS, and responded sensitively to viscosity. Notably, dicationic TTP‐M showed enhanced lipophilicity, superior cellular uptake, thereby exerting strong PDT cytotoxicity and inducing apoptosis and pyroptosis upon white light irradiation. To enhance in vivo applicability, TTP‐M was encapsulated with DSPE‐mPEG 2000 to form TTP‐M nanoparticles ( TTP‐M NPs), which preserved strong phototoxicity while markedly enhancing aqueous dispersibility, biocompatibility, and tumor‐targeting capability. In 4T1 tumor‐bearing mice, TTP‐M NPs exhibited high tumor‐targeting accumulation and significant tumor growth inhibition without noticeable systemic toxicity. In summary, this work validates dual‐organelle targeting as an effective strategy to overcome ROS diffusion limitations and enhancing PDT efficacy, offering a feasible molecular design approach for developing highly efficient, biocompatible and safe PDT agents for precision cancer therapy.