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

ABSTRACT 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 Fe ²⁺ 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.