Wang Wenyan, Yao Shun-Yu, Luo Jingjing, Ding Chendi, Huang Qili, Yang Yao, Shi Zhaoqing, Lin Jiachan, Pan Yu-Chen, Zeng Xiaowei, Guo Dong-Sheng, Chen Hongzhong
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Frontiers Science Center for New Organic Matter, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, China.
Nat Commun. 2025 Jan 11;16(1):596. doi: 10.1038/s41467-025-55905-y.
Hypoxic tumors present a significant challenge in cancer therapy due to their ability to adaptation in low-oxygen environments, which supports tumor survival and resistance to treatment. Enhanced mitophagy, the selective degradation of mitochondria by autophagy, is a crucial mechanism that helps sustain cellular homeostasis in hypoxic tumors. In this study, we develop an azocalix[4]arene-modified supramolecular albumin nanoparticle, that co-delivers hydroxychloroquine and a mitochondria-targeting photosensitizer, designed to induce cascaded oxidative stress by regulating mitophagy for the treatment of hypoxic tumors. These nanoparticles are hypoxia-responsive and release loaded guest molecules in hypoxic tumor cells. The released hydroxychloroquine disrupts the mitophagy process, thereby increasing oxidative stress and further weakening the tumor cells. Additionally, upon laser irradiation, the photosensitizer generates reactive oxygen species independent of oxygen, inducing mitochondria damage and mitophagy activation. The dual action of simultaneous spatiotemporal mitophagy activation and mitophagy flux blockade results in enhanced autophagic and oxidative stress, ultimately driving tumor cell death. Our work highlights the effectiveness of hydroxychloroquine-mediated mitophagy blockade combined with mitochondria-targeted photosensitizer for cascade-amplified oxidative stress against hypoxic tumors.
由于缺氧肿瘤能够在低氧环境中适应，这支持了肿瘤的存活和对治疗的抗性，因此在癌症治疗中构成了重大挑战。增强的线粒体自噬，即通过自噬选择性降解线粒体，是一种关键机制，有助于维持缺氧肿瘤中的细胞稳态。在本研究中，我们开发了一种偶氮杯[4]芳烃修饰的超分子白蛋白纳米颗粒，其共同递送羟氯喹和一种线粒体靶向光敏剂，旨在通过调节线粒体自噬来诱导级联氧化应激，用于治疗缺氧肿瘤。这些纳米颗粒对缺氧有响应，并在缺氧肿瘤细胞中释放负载的客体分子。释放的羟氯喹破坏线粒体自噬过程，从而增加氧化应激并进一步削弱肿瘤细胞。此外，在激光照射下，光敏剂产生不依赖于氧气的活性氧，诱导线粒体损伤和线粒体自噬激活。同时进行时空线粒体自噬激活和线粒体自噬通量阻断的双重作用导致自噬和氧化应激增强，最终驱动肿瘤细胞死亡。我们的工作突出了羟氯喹介导的线粒体自噬阻断与线粒体靶向光敏剂相结合对缺氧肿瘤进行级联放大氧化应激的有效性。
