Ferroptosis, a newly discovered form of regulated cell death, is emerging as a promising approach to tumor therapy. However, the spatiotemporal control of cell-intrinsic Fenton chemistry to modulate tumor ferroptosis remains challenging. Here, we report an oxazine-based activatable molecular assembly (PTO-Biotin Nps), which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway with excellent spatiotemporal resolution via near-infrared (NIR) light to evoke ferroptosis. In this system, a pH-responsive NIR photothermal oxazine molecule was designed and functionalized with a tumor-targeting hydrophilic biotin-poly(ethylene glycol) (PEG) chain to engineer well-defined nanostructured assemblies within a single-molecular framework. PTO-Biotin Nps possesses a selective tropism to lysosome accumulation inside tumor cells, accommodated by its enhanced photothermal activity in the acidic microenvironment. Upon NIR light activation, PTO-Biotin Nps promoted lysosomal dysfunction and induced cytosolic acidification and impaired autophagy. More importantly, photoactivation-mediated lysosomal dysfunction via PTO-Biotin Nps was found to markedly enhance cellular Fenton reactions and evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects. Overall, our study demonstrates that the molecular engineering approach of pH-responsive photothermal oxazine assemblies enables the spatiotemporal modulation of the intrinsic ferroptosis mechanism, offering a novel strategy for the development of metal-free Fenton inducers in antitumor therapy.
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