Rational Design of Porphyrin‐Based Nano‐Prodrug for Overcoming ROS Resistance and Synergistic Photodynamic Cancer Therapy

ABSTRACT Porphyrin‐based photosensitizers (PSs) are among the most widely explored agents for photodynamic therapy (PDT), yet their clinical translation is severely limited by poor biocompatibility, aggregation‐induced quenching, insufficient tumor selectivity, and the intrinsic reactive oxygen species (ROS) resistance of cancer cells. Herein, we report a tumor microenvironment (TME)‐responsive self‐assembly nano‐prodrug that integrates a porphyrin PS with sulfasalazine (SSZ), an inhibitor of the SLC7A11‐GSH‐GPX4 antioxidant pathway, to achieve amplified and sustained PDT efficacy. A TME‐activatable porphyrin prodrug was rationally engineered with a pyridinium linker, enabling spontaneous co‐assembly with SSZ through strong π‐π stacking interactions to form positively charged nanoparticles. Subsequent hyaluronic acid (HA) coating endowed the system with enhanced colloidal stability, prolonged circulation, and tumor targeting. Upon intracellular uptake, elevated glutathione (GSH) levels in tumor cells triggered prodrug activation, restoring porphyrin photodynamic activity and fluorescence for tumor‐specific theranostic imaging. Under light irradiation, efficient ROS generation was synergistically reinforced by SSZ‐mediated suppression of intracellular antioxidant defenses, leading to pronounced oxidative damage. In vivo studies demonstrated potent antitumor and anti‐metastatic efficacy with minimal systemic toxicity. This work highlights a versatile self‐assembly nano‐prodrug strategy that overcomes both physicochemical and biological barriers of porphyrin‐based PDT, offering a promising platform for precision phototheranostics.