Nicotinamide-derived tumor-targeting carbon dots for Cancer Photothermal therapy.

The lack of tumor-specific targeting remains a major bottleneck in photothermal therapy. Here, we exploit the natural affinity of nicotinamide (NAM) for Ki67, a tumor proliferation marker, to design a targeted photothermal nanomaterial. NAM-derived carbon dots (NAM-CDs) were synthesized via a one-step solvothermal method, in which the carbon core serves as a scaffold for the multivalent presentation of NAM moieties. Dynamic molecular docking simulations revealed that NAM-CDs exhibited a markedly enhanced binding affinity toward Ki67, with binding energy of -7.7 kcal/molcompared with -3.8 kcal/mol for free NAM. These results indicate that the multivalent display of NAM not only preserves but also amplifies its intrinsic Ki67-targeting capability. To further optimize the photophysical properties of NAM-CDs, the synthesis temperature was systematically tuned. At 180 °C, the resulting NAM-CDs developed a pyridine-rich surface characterized by maximized pyrrolic-N content and enhanced amide bond formation, facilitating efficient energy transfer from the carbon core to surface states. This optimized electronic structure synergistically enhanced both red fluorescence emission and photothermal conversion efficiency. The pyridine-rich NAM-CDs exhibited excellent biocompatibility, specific nuclear retention through Ki67-mediated interactions in cancer cells, and potent photothermal tumor ablation upon 660 nm laser irradiation in vivo, achieving complete tumor regression without recurrence over a 30-day observation period. By harnessing the inherent Ki67 affinity of NAM, this work provides a facile strategy for imparting tumor-targeting capability to photothermal agents, opening a new avenue for proliferation-marker-directed cancer therapy.