Wang Huanhuan, Zhang Ting, Zhuang Yan, Chen Zhuoyu, Qu Rumeng, Mai Yuanyuan, Wu Baoyan, Sun Beini, Chen Tongsheng
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, No.55 West Zhongshan Avenue, Tianhe District, Guangzhou 510631, Guangdong, China.
Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, No. 55 West Zhongshan Avenue, Tianhe District, Guangzhou 510631, Guangdong, China.
ACS Appl Mater Interfaces. 2025 Sep 17;17(37):51854-51865. doi: 10.1021/acsami.5c13514. Epub 2025 Sep 8.
While reactive oxygen species (ROS)-dependent chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold promise for cancer treatment, their efficacy remains constrained by tumor microenvironment (TME) barriers: glutathione (GSH) overexpression, insufficient HO supply, and hypoxia. To address these limitations, we engineered a Trojan horse-inspired MnO-shelled CaO nanoreactor (CaO/MnO-Ce6-PEG) by employing a sequential TME reprogramming strategy, triggering a cascading ROS storm for enhanced CDT and PDT. The outer MnO layer first depletes GSH through redox conversion, exposing the CaO core hydrolysis, and subsequently providing HO for CDT and O for ameliorating hypoxia to boost Ce6-mediated PDT. studies demonstrate that the nanoreactor enables efficient cellular internalization and intracellular GSH depletion with continuous HO/O generation, achieving synergistic CDT and PDT in malignant cells. studies show that the nanoreactor potently inhibits tumor growth in murine tumor models with negligible systemic toxicity, due to Trojan horse architecture enabling TME-responsive shell dissociation and spatiotemporally controlled payload release. The rationally designed nanoreactor enables triple-enhanced CDT/PDT via TME-reprogramming capabilities: GSH-mediated antioxidant defense blockade, ROS precursor replenishment, and hypoxia reversal. This work provides a self-reinforcing platform by dynamically reprogramming multiple TME barriers to ROS-based anticancer therapy.
虽然依赖活性氧（ROS）的化学动力学疗法（CDT）和光动力疗法（PDT）在癌症治疗方面具有前景，但其疗效仍受到肿瘤微环境（TME）屏障的限制：谷胱甘肽（GSH）过表达、羟基自由基（HO）供应不足和缺氧。为了解决这些限制，我们采用了一种顺序TME重编程策略，设计了一种受特洛伊木马启发的MnO壳CaO纳米反应器（CaO/MnO-Ce6-PEG），引发级联ROS风暴以增强CDT和PDT。外层MnO首先通过氧化还原转化消耗GSH，使CaO核心水解，随后为CDT提供HO并为改善缺氧提供氧气以增强Ce6介导的PDT。研究表明，该纳米反应器能够实现有效的细胞内化和细胞内GSH消耗，并持续产生HO/O，在恶性细胞中实现协同CDT和PDT。研究表明，由于特洛伊木马结构能够实现TME响应性壳解离和时空控制的载荷释放，该纳米反应器在小鼠肿瘤模型中能有效抑制肿瘤生长，且全身毒性可忽略不计。合理设计的纳米反应器通过TME重编程能力实现三重增强的CDT/PDT：GSH介导的抗氧化防御阻断、ROS前体补充和缺氧逆转。这项工作通过动态重编程多个TME对基于ROS的抗癌治疗的屏障，提供了一个自我强化的平台。
