Zhu Piao, Pu Yinying, Wang Min, Wu Wencheng, Qin Huanlong, Shi Jianlin
Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200331, P. R. China.
Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai 200072, P. R. China.
J Am Chem Soc. 2023 Mar 15;145(10):5803-5815. doi: 10.1021/jacs.2c12942. Epub 2023 Feb 27.
The antioxidant system, signed with reduced glutathione (GSH) overexpression, is the key weapon for tumor to resist the attack by reactive oxygen species (ROS). Counteracting the ROS depletion by GSH is an effective strategy to guarantee the antitumor efficacy of nanocatalytic therapy. However, simply reducing the concentration of GSH does not sufficiently improve tumor response to nanocatalytic therapy intervention. Herein, a well-dispersed MnOOH nanocatalyst is developed to catalyze GSH autoxidation and peroxidase-like reaction concurrently and respectively to promote GSH depletion and HO decomposition to produce abundant ROS such as hydroxyl radical (·OH), thereby generating a highly effective superadditive catalytic therapeutic efficacy. Such a therapeutic strategy that transforms endogenous "antioxidant" into "oxidant" may open a new avenue for the development of antitumor nanocatalytic medicine. Moreover, the released Mn can activate and sensitize the cGAS-STING pathway to the damaged intratumoral DNA double-strands induced by the produced ROS to further promote macrophage maturation and M1-polarization, which will boost the innate immunotherapeutic efficacy. Resultantly, the developed simple MnOOH nanocatalytic medicine capable of simultaneously catalyzing GSH depletion and ROS generation, and mediating innate immune activation, holds great potential in the treatment of malignant tumors.
以还原型谷胱甘肽（GSH）过表达为特征的抗氧化系统是肿瘤抵抗活性氧（ROS）攻击的关键武器。对抗GSH导致的ROS耗竭是保证纳米催化治疗抗肿瘤疗效的有效策略。然而，单纯降低GSH浓度并不能充分提高肿瘤对纳米催化治疗干预的反应。在此，开发了一种分散良好的MnOOH纳米催化剂，以同时分别催化GSH自氧化和类过氧化物酶反应，促进GSH耗竭和HO分解，产生大量的ROS，如羟基自由基（·OH），从而产生高效的超加性催化治疗效果。这种将内源性“抗氧化剂”转化为“氧化剂”的治疗策略可能为抗肿瘤纳米催化药物的开发开辟一条新途径。此外，释放的Mn可以激活并使cGAS-STING通路对由产生的ROS诱导的肿瘤内DNA双链损伤敏感，以进一步促进巨噬细胞成熟和M1极化，这将增强先天免疫治疗效果。因此，所开发的能够同时催化GSH耗竭和ROS生成并介导先天免疫激活的简单MnOOH纳米催化药物在恶性肿瘤治疗中具有巨大潜力。
