Copper-Peptide Assemblies with Self-Driven Signal Release for Electrochemical Analysis of Exosomes

Abstract Multifunctional peptides have garnered considerable attention owing to their excellent biocompatibility and unique physicochemical properties. Herein, we report an electrochemical method for the sensitive detection of exosomes based on copper-peptide assemblies with a self-driven signal release approach. In the design, an engineered histidine-rich peptide coordinates with Cu2+ to self-assemble into pH-responsive nanoparticles (Cu-Pep). Upon target exosome recognition, an aptamer-triggered terminal deoxynucleotidyl transferase-mediated polymerization cascade is initiated. The protons generated during this process then lower the local pH, which in turn drives the autonomous disassembly of Cu-Pep and releases abundant Cu2+, producing a greatly amplified electrochemical signal readout. Benefiting from this ingenious self-driven cascade amplification, the method achieves an impressive limit of detection of 41 particles/μL, alongside outstanding selectivity and reproducibility. Furthermore, it can successfully differentiate exosomes among breast cancer patients, healthy controls, and post-treatment individuals in clinical serum samples, offering a powerful, non-invasive liquid biopsy strategy for diagnosis and therapeutic monitoring of the cancer.