Solanum nigrum ‐Derived Carbon Dots Alleviate Tumor Hypoxia to Potentiate Photodynamic Therapy in Esophageal Squamous Cell Carcinoma

ABSTRACT Esophageal squamous cell carcinoma (ESCC) is highly prevalent and aggressive in China, with conventional therapies causing significant morbidity. Photodynamic therapy (PDT) kills tumor cells via photosensitizer‐mediated reactive oxygen species (ROS), representing an effective tumor treatment. However, its efficacy is severely impaired by the hypoxic tumor microenvironment (TME). In this study, we synthesized multifunctional carbon dots (SN‐CDs) from the traditional Chinese herb Solanum nigrum via hydrothermal method. SN‐CDs (particle size: 1.9 ± 0.3 nm) are rich in hydroxyl and amino groups, with an oxygen generation rate of approximately 2.61 ppm/min in vitro. They can efficiently decompose endogenous hydrogen peroxide in the tumor microenvironment, thereby alleviating tumor hypoxia. Under 635 nm laser irradiation, they generate ROS ( 1 O 2 , ·OH). In vitro, SN‐CDs induce apoptosis in ESCC cells (EC9706/EC109) and regulate HIF‐1 pathway (downregulate VEGFA, upregulate CDKN1B). In vivo, SN‐CD‐mediated PDT reduces ESCC xenograft volume by 60% with no obvious systemic toxicity observed in vivo. Thus, SN‐CDs are a natural, multifunctional nanoplatform that alleviates tumor hypoxia to enhance PDT efficacy, promising for minimally invasive ESCC treatment.