Photothermally Triggered Intratumoral In Situ Drug Synthesis: A Smart Nanoplatform for NIR‐Controlled Precise Activation of Antitumor Precursors

To enable the biomedical application of hydrophobic antitumor agents and expand organic reactions in physiological settings, we engineered an NIR-responsive nanoplatform (Fe-MSN^Y6-OPD/benzil@PEG-AS1411, FOBA) for on-demand intratumoral drug synthesis. The system utilizes an iron-doped mesoporous silica framework co-loaded with photothermal converter Y6 and hydrophobic precursors (o-phenylenediamine/benzil), surface-coated with high-M_W PEG as a stimuli-responsive gatekeeper. Upon 808 nm NIR laser irradiation, Y6-mediated photothermal heating induces PEG phase transition, creating a transient solvent microenvironment that enables in situ synthesis of the cytotoxic agent 2,3-diphenylquinoxaline (2,3-DPQ) selectively within tumors. Concurrently, the nanoplatform degrades to release Fe²⁺ ions, inducing synergistic ferroptosis alongside drug synthesis. In vitro and in vivo studies demonstrate excellent biocompatibility and precise spatiotemporal control of therapeutic activation. By integrating rapid, localized drug generation with slow-hydrolysis-mediated ferroptosis, this dual-temporal strategy expands the applicability of hydrophobic compounds and organic chemistry for precision nanomedicine.