Cationic Photosensitizer-Functionalized Bacteria for Targeted Photothermal-Photodynamic Therapy with Immune Activation.

Bacteria possess innate tumor tropism and immunostimulatory properties, yet their efficacy as monotherapy is limited. Here, we report rational cationic interface engineering of bacteria through a tricationic heptamethine photosensitizer (Cy-HEX) to construct a well-defined bacteria-photosensitizer hybrid (VNP@Cy-HEX). Tricationic modification strengthens bacterial adhesion and solubility, stabilizing the hybrid and promoting tumor accumulation through motility and hypoxia-directed localization. Under near-infrared irradiation (785 nm), Cy-HEX mediates simultaneous photothermal (η = 54.9%) and photodynamic effects and displays robust photostability. VNP@Cy-HEX induces immunogenic cell death, promotes dendritic-cell maturation, and amplifies T-cell activation, ultimately leading to substantial solid tumor regression (94.4% inhibition in vivo). This work demonstrates that cationic photosensitizer-functionalized bacteria can enhance bacterial tumor targeting and photoimmune therapeutic efficacy, providing a chemically guided strategy for bacteria-based cancer treatment.