Chen Yichi, Wang Yijun, Zhang Ruotian, Wang Fengyi, Lin Xin, Wang Tong, Zhang Wenyuan, Deng Fuan, Wu Bolin, Shang Haitao, Cheng Wen, Zhang Lu
Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.
Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China.
Small. 2025 Jan;21(1):e2406802. doi: 10.1002/smll.202406802. Epub 2024 Nov 3.
Dysregulation of copper metabolism is intricately associated with the occurrence and therapeutic management of colorectal cancer. Previous studies have attempted to induce cuproptosis by delivering lethal doses of copper ions into tumor cells, often with systemic safety risks. In vivo, transformable peptide is modular and designed for various tumor-related proteins, which can affect protein function and distribution. Here, a fibrillar transformation peptidic (FTP) nanoparticle is synthesized, which can bind ATP7B membrane proteins (cuprous ions transporter) and transform into nanofibrils/ATP7B clusters, inducing "copper-free cuproptosis" in vivo. Without adding exogenous copper ions, the spherical FTP nanoparticles bound the high distribution regions of ATP7B membrane proteins, transforming into fibrillar networks in situ with prolonged retention. The cage-like fibrillar network would further capture unbound or newly generated free ATP7B membrane proteins, thereby significantly and consistently preventing cuprous ions efflux. The FTP nanoparticles would not undergo in situ fibrillar transformation on the low expression region of ATP7B membrane proteins but enter the cell for safe degradation, which exhibited high specificity and safety in vivo. By disrupting intracellular copper homeostasis, the transformable fibrillar clusters displayed a long-term anti-tumor effect on subcutaneous transplantation and liver metastatic CRC models.
铜代谢失调与结直肠癌的发生及治疗密切相关。以往的研究试图通过向肿瘤细胞输送致死剂量的铜离子来诱导铜死亡，但往往存在全身安全风险。在体内，可转化肽具有模块化特点，针对各种肿瘤相关蛋白进行设计，能够影响蛋白质的功能和分布。在此，合成了一种纤维状转化肽（FTP）纳米颗粒，它可以结合ATP7B膜蛋白（铜离子转运体）并转化为纳米纤维/ATP7B簇，在体内诱导“无铜铜死亡”。在不添加外源铜离子的情况下，球形的FTP纳米颗粒结合ATP7B膜蛋白的高分布区域，原位转化为纤维状网络并长时间滞留。笼状的纤维状网络会进一步捕获未结合的或新产生的游离ATP7B膜蛋白，从而显著且持续地阻止铜离子外流。FTP纳米颗粒在ATP7B膜蛋白低表达区域不会发生原位纤维状转化，而是进入细胞进行安全降解，在体内表现出高特异性和安全性。通过破坏细胞内铜稳态，可转化的纤维状簇对皮下移植和肝转移结直肠癌模型显示出长期的抗肿瘤作用。
