Stimuli‐Responsive Nanoplatform for Photodynamic Therapy and Disulfidptosis Synergy

ABSTRACT Photodynamic therapy (PDT) is an effective strategy for eliminating primary tumors, but local hypoxia within tumor tissues significantly limits its efficacy. Additionally, premature leakage of photosensitizers (PS) from nanocarriers not only reduces their targeted accumulation in tumors, but also increases their nonspecific distribution in healthy tissues, which further impairs the efficiency of PDT and enhances systemic phototoxicity. Herein, we have developed a highly efficient and specific nanoplatform for cancer therapy. This platform utilizes polyethylene glycol‐modified gold nanoparticles (AuNPs) as carriers, coated with a multifunctional shell that controls the release of the photosensitizer Chlorin e6 (Ce6) and modulates tumor hypoxia. This design overcomes two key limitations of PDT: premature PS leakage and local hypoxia in the tumor microenvironment. By catalyzing the decomposition of endogenous hydrogen peroxide (H 2 O 2 ) within tumors, the platform generates oxygen, thereby alleviating hypoxia and enhancing Ce6’s ability to generate reactive oxygen species (ROS) under near‐infrared irradiation. Moreover, the glucose oxidase‐like activity of AuNPs induces glucose depletion in tumor cells, promoting disulfidptosis, a form of cell death triggered by disulfide stress. In vitro experiments demonstrate that the nanoplatform selectively induces cancer cell death without affecting normal cells, underscoring its excellent biocompatibility and therapeutic potential. These findings suggest that the combination of controlled Ce6 release, hypoxia alleviation, and glucose depletion significantly enhances the efficacy of PDT, providing a novel cancer treatment strategy with broad applications to address the challenges of hypoxia and premature drug release.