A Cascade‐Responsive Carbon Dot‐Nanogel Platform for Sequential Photothermal‐Chemo Cancer Therapy via GSH and NIR Dual Activation

Chemotherapeutic agents are often limited by poor tumor-specific accumulation, leading to off-target toxicity, while monochemotherapy frequently results in multidrug resistance and suboptimal treatment outcomes. To address these challenges, we have developed a carbon dot-based nanogel drug delivery system that integrates both glutathione (GSH) and photothermal dual-responsiveness, enabling controlled drug release, active tumor targeting, and synergistic photothermal-chemotherapy. Specifically, phenylboronic acid functionalized on the nanogel surface confers tumor-targeting capability. Upon internalization into tumor cells with elevated GSH levels, the nanogel disintegrates, releasing carbon dots conjugated with the chemotherapeutic drug doxorubicin (DOX). Under near-infrared (NIR) irradiation, the carbon dots generate heat, which not only directly damages cancer cells but also triggers on-demand DOX release, achieving a synergistic photothermal-chemotherapeutic effect. Notably, both in vitro and in vivo studies reveal that this system effectively induces cancer cell necrosis through a multimodal mechanism: disruption of lysosomes, induction of DNA damage, and simultaneous suppression of heat shock protein (HSP) expression. This integrated strategy results in significantly enhanced therapeutic outcomes, overcoming key limitations of conventional chemotherapy.