Glycosylated β-C₃N₄ carbon nanodots for warburg effect-driven photothermal therapy of tumors

• β-C3N4 CDs show biocompatibility, tunable red fluorescence, and photothermal behavior. • Controlled surface glycosylation enables targeted uptake in breast cancer. • Surface engineering of CDs enhances uptake in breast cancer cells. • Surface regioisomerism of glucose moieties tune CDs’ affinity for GLUT1 receptors. • Glycosylated CDs enable mild hyperthermia for precise photothermal therapy. Harnessing self-trackable nanomaterials capable of converting light into heat for cancer photothermal therapy (PTT) offers a non-invasive, selective, and tunable therapeutic approach in precision medicine. However, successful clinical translation of theranostic agents for image-guided cancer PTT requires proving safety, efficacy, scalable production, and strong tumor targeting driven by metabolic activity or receptor binding. Here, we report a comprehensive evaluation of homogeneous carbon nanodots with β-C₃N₄ crystalline structure, tunable multicolor fluorescence, high cytocompatibility, and efficient photothermal conversion as a theranostic nanoplatform for PTT applications. Optimizing the irradiation parameters to selectively reach mild-hyperthermia conditions (42–49 °C), we achieved controlled antitumoral effects in triple-negative breast cancer cells. The developed nanoheater was further conjugated with 2-deoxy- or 6-deoxy-D-glucose to enhance tumor targeting via GLUT1-mediated uptake, leveraging the abnormal glucose metabolism of cancer cells (Warburg effect). Glycosylation did not compromise CDs’ optical properties, resulting in a nanostructure with ideal physical characteristics for PTT applications. In vitro assays on 2D and 3D models validated the active targeting strategy adopted and the photothermal efficacy of the nanosystems, also emphasizing a superior performance for CDs-6-Glu with respect to CDs-2-Glu. Altogether, this study aims to advance the development of safer, bioeliminable, more selective, and precisely controllable photothermal therapies through the rational design of glycosylated carbon nanodots tailored for targeted cancer treatment.