National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, P. R. China.
National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, School of Physics, Nanjing University, Nanjing 210093, P. R. China.
ACS Appl Mater Interfaces. 2023 Feb 8;15(5):6456-6472. doi: 10.1021/acsami.2c19638. Epub 2023 Jan 26.
Better understanding of important roles of metabolic reprogramming in therapeutic resistance provides insights into advancing cancer treatment. Herein, we present a photoactive metabolic reprogramming strategy (termed as photometabolism therapy, PMT), in which photoregulation of mitochondria leads to cancer cell metabolic crisis, and consequently overcomes therapeutic resistance while improving treatment efficacy. In specific, a stimuli-responsive metabolism NanoValve is developed for improving cascade cancer therapy through blocking mitochondrial energy supply. NanoValve is composed of an onion-like architecture with a gold nanorod core, a mesoporous silica shell encapsulating photosensitizer chlorin e6 and oxygen-saturated perfluorocarbon, and cationic liposomal coating with MMP2-cleavable polyethylene glycol corona, which together initiate mitochondria-specific PMT. NanoValve selectively responds to tumor-overexpressed MMP2 and achieves size decrease and charge reversal, which consequently enhances tumor penetration, cancer cell uptake, endosome escape, and most critically, mitochondrial accumulation. Importantly, NanoValve-mediated phototherapy can strongly destruct mitochondrial energy metabolism, thereby minimizing therapy resistance. Particularly, perfluorocarbon supplies oxygen to further overcome the tumor hypoxia-associated therapeutic barrier and maximizes synergistic anticancer effects. In vivo studies show that NanoValve can effectively eliminate tumors without side effects, thereby dramatically prolonging the survival of tumor-bearing mice. Thus, NanoValve provides a modular PMT approach and has the potential of advancing the treatment of malignancy.
更好地理解代谢重编程在治疗抵抗中的重要作用，为推进癌症治疗提供了新的思路。在此，我们提出了一种光激活代谢重编程策略（称为光代谢治疗，PMT），其中线粒体的光调控导致癌细胞代谢危机，从而克服治疗抵抗，同时提高治疗效果。具体而言，我们开发了一种对刺激响应的代谢纳米阀，通过阻断线粒体能量供应来提高级联癌症治疗效果。纳米阀由洋葱状结构组成，具有金纳米棒核、包裹光敏剂叶绿素 e6 和氧饱和全氟碳的介孔硅壳，以及带有 MMP2 可切割聚乙二醇冠的阳离子脂质体涂层，共同引发线粒体特异性 PMT。纳米阀选择性地响应肿瘤过表达的 MMP2，并发生尺寸减小和电荷反转，从而增强肿瘤穿透、癌细胞摄取、内体逃逸，最重要的是，线粒体积累。重要的是，纳米阀介导的光疗可以强烈破坏线粒体能量代谢，从而最大限度地减少治疗抵抗。特别地，全氟碳为进一步克服与肿瘤缺氧相关的治疗障碍提供氧气，并最大限度地提高协同抗癌效果。体内研究表明，纳米阀能够有效消除肿瘤而无副作用，从而显著延长荷瘤小鼠的存活时间。因此，纳米阀提供了一种模块化的 PMT 方法，具有推进恶性肿瘤治疗的潜力。
