Zhao Zhihao, Ling Ke, Yan Jun, Wang Zhexiang, Chen Chuntao, Sun Dongping, Liu Jian
Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu Province 215123, China.
Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu Province 215123, China.
Acta Biomater. 2025 Jul 1;201:545-558. doi: 10.1016/j.actbio.2025.06.009. Epub 2025 Jun 16.
Calcium ions (Ca²⁺) and reactive oxygen species (ROS) play pivotal roles in cellular signaling and the regulation of diverse biological processes. Complex and dynamic interactions between Ca²⁺ and ROS signaling pathways are often exploited by tumor cells to resist therapeutic interventions. In this study, we present a strategy of cancer treatment based on the reciprocally reinforcing interplay between ROS burst and mitochondrial calcium overload. The major components of our nano carriers integrate CaCO nanoparticles loaded with glucose oxidase (GOx), and copper peroxide nanodots (CPDs) in a DSPE-S-S-PEG-modified liposomal format (abbr. GCCL,). This hybrid nanosystem is designed to facilitate controlled and accelerated release of Ca²⁺ and ROS, thereby establishing dual positive feedback loops that amplify both mitochondrial calcium accumulation and oxidative stress. By harnessing this synergistic cycle, our platform enhances the efficacy of chemodynamic therapy and calcium-induced mitochondrial damage, offering a promising strategy for translational cancer treatment. STATEMENT OF SIGNIFICANCE: Here we report a strategy of antitumor therapeutic by designing a dual positive feedback loop of pH-driven self-accelerated Ca and HO release, thus reciprocally promoting ROS production and mitochondrial calcium overload for tumor eradication. After cellular uptake of GCCL, releasing of the cargos inside the liposomes can introduce a cascade of chemical reactions and biochemical cues, leading to calcium overload and ROS burst. These two major effects are mutually linked with each other, which is utilized by our GCCL design to fuel the positive feedback loops for tumor cell apoptosis in vitro and effective cancer ablation in vivo. Our nano therapy stands out with improved tumor suppression, with a lower dosage of copper element in the treatments of 4T1 xenograft tumor-bearing BALB/c mice model.
钙离子（Ca²⁺）和活性氧（ROS）在细胞信号传导及多种生物过程的调节中发挥着关键作用。肿瘤细胞常常利用Ca²⁺与ROS信号通路之间复杂而动态的相互作用来抵抗治疗干预。在本研究中，我们提出了一种基于ROS爆发与线粒体钙超载之间相互增强作用的癌症治疗策略。我们纳米载体的主要成分将负载葡萄糖氧化酶（GOx）的碳酸钙纳米颗粒和过氧化铜纳米点（CPD）整合到DSPE-S-S-PEG修饰的脂质体形式中（简称GCCL）。这种混合纳米系统旨在促进Ca²⁺和ROS的可控加速释放，从而建立双重正反馈回路，放大线粒体钙积累和氧化应激。通过利用这种协同循环，我们的平台提高了化学动力疗法和钙诱导的线粒体损伤的疗效，为转化癌症治疗提供了一种有前景的策略。重要性声明：在此我们报告一种抗肿瘤治疗策略，通过设计pH驱动的自加速Ca和HO释放的双重正反馈回路，从而相互促进ROS产生和线粒体钙超载以根除肿瘤。GCCL被细胞摄取后，脂质体内货物的释放可引发一系列化学反应和生化信号，导致钙超载和ROS爆发。这两种主要效应相互关联，我们的GCCL设计利用这一点来推动正反馈回路，以实现体外肿瘤细胞凋亡和体内有效癌症消融。我们的纳米疗法在肿瘤抑制方面表现突出，在4T1异种移植荷瘤BALB/c小鼠模型的治疗中使用较低剂量的铜元素。
