In Situ Transformable Fibrillar Clusters Disrupt Intracellular Copper Metabolic Homeostasis by Comprehensive Blockage of Cuprous Ions Efflux

Abstract 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.