State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
J Am Chem Soc. 2023 Feb 15;145(6):3736-3747. doi: 10.1021/jacs.2c13222. Epub 2023 Feb 2.
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 (), 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. possesses a selective tropism to lysosome accumulation inside tumor cells, accommodated by its enhanced photothermal activity in the acidic microenvironment. Upon NIR light activation, promoted lysosomal dysfunction and induced cytosolic acidification and impaired autophagy. More importantly, photoactivation-mediated lysosomal dysfunction via 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.
铁死亡是一种新发现的细胞程序性死亡形式，作为肿瘤治疗的一种有前途的方法正在兴起。然而，细胞内芬顿化学的时空控制来调节肿瘤铁死亡仍然具有挑战性。在这里，我们报告了一种基于恶嗪的可激活分子组装体（），它能够通过近红外（NIR）光以优异的时空分辨率触发溶酶体功能障碍介导的芬顿途径，从而引发铁死亡。在该系统中，设计了一种 pH 响应的 NIR 光热恶嗪分子，并将其功能化与肿瘤靶向亲水性生物素-聚乙二醇（PEG）链，以在单个分子框架内工程设计具有良好定义的纳米结构组装体。 具有对肿瘤细胞内溶酶体积累的选择性趋向性，这与其在酸性微环境中的增强光热活性有关。在 NIR 光激活后， 促进溶酶体功能障碍，并诱导细胞质酸化和受损的自噬。更重要的是，通过 介导的光激活溶酶体功能障碍显著增强了细胞内的芬顿反应，并引发铁死亡，从而提高了抗肿瘤疗效并减轻了全身副作用。总的来说，我们的研究表明，pH 响应光热恶嗪组装体的分子工程方法能够实现内在铁死亡机制的时空调节，为开发金属免费芬顿诱导剂在抗肿瘤治疗中提供了一种新策略。
