Shen Qi, Zhu Xi, Huo Mengping, Lin Yafei, Zhang Wenting, Yang Ming, Zhang Yang, Zhang Long, Gai Yonghao
Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan Shandong 250021 P. R. China
Institute of Biomedical Engineering, Kunming Medical University Kunming Yunnan 650500 P. R. China.
RSC Adv. 2025 Mar 27;15(12):9408-9419. doi: 10.1039/d5ra00032g. eCollection 2025 Mar 21.
Ferroptosis, a novel form of cell death driven by lipid peroxides (LPO) accumulation, holds promise for personalized cancer therapy. However, its efficacy is constrained by the tumor microenvironment (TME), which is characterized by hypoxia, insufficient endogenous hydrogen peroxide (HO), and glutathione (GSH) overabundance. To address these limitations, we developed a multifunctional nanoplatform, HMnO-VC@mPEG-Ce6 (HMVC), which integrates sono-chemodynamic strategies to induce synergistic ferroptosis in prostate cancer. The therapeutic superiority of HMVC stems from three coordinated mechanisms. Firstly, HMnO catalyze HO decomposition to generate oxygen (O), alleviating tumor hypoxia and amplifying the sonodynamic effect of chlorin e6 (Ce6). Secondly, vitamin C (VC) sustains HO production chemodynamic therapy (CDT), driving a burst of reactive oxygen species (ROS). Thirdly, GSH-triggered reduction of Mn to Mn depletes GSH reserves and suppresses glutathione peroxidase 4 (GPX4) activity. These cascading actions disrupt the ROS-GPX4 equilibrium, leading to irreversible LPO accumulation and subsequent ferroptosis. Our work establishes a generalizable nanotechnology paradigm to overcome TME barriers and achieve precise ferroptosis regulation, offering a transformative strategy for cancer treatment.
铁死亡是一种由脂质过氧化物（LPO）积累驱动的新型细胞死亡形式，为个性化癌症治疗带来了希望。然而，其疗效受到肿瘤微环境（TME）的限制，肿瘤微环境的特征是缺氧、内源性过氧化氢（HO）不足和谷胱甘肽（GSH）过量。为了解决这些限制，我们开发了一种多功能纳米平台HMnO-VC@mPEG-Ce6（HMVC），它整合了声化学动力学策略，以在前列腺癌中诱导协同铁死亡。HMVC的治疗优势源于三种协同机制。首先，HMnO催化HO分解产生氧气（O），缓解肿瘤缺氧并增强二氢卟吩e6（Ce6）的声动力效应。其次，维生素C（VC）通过化学动力学疗法（CDT）维持HO的产生，引发活性氧（ROS）爆发。第三，GSH触发的Mn向Mn的还原消耗了GSH储备并抑制了谷胱甘肽过氧化物酶4（GPX4）的活性。这些级联作用破坏了ROS-GPX4平衡，导致不可逆的LPO积累和随后的铁死亡。我们的工作建立了一种可推广的纳米技术范式，以克服TME障碍并实现精确的铁死亡调节，为癌症治疗提供了一种变革性策略。
