Self-cascade nanozyme electrochemical platform with antifouling COFs-derived nanohydrogel: High-precision detection of circulating SAPs for breast cancer metastasis prediction.

Breast cancer following metastatic dissemination is associated with high mortality rates, severely threatening women's health. As principal mediators of intercellular communication within the tumor microenvironment, secretory autophagosomes (SAPs) propel breast cancer progression and metastasis by modulating the establishment of the pre-metastatic niche, thereby positioning them as highly promising biomarkers for breast cancer. However, the paucity of accurate and simplified quantitative tools has impeded the direct detection of circulating SAPs. This study presents a sensing platform that couples nanozyme cascade catalysis with a covalent organic frameworks (COFs)-derived nanohydrogel (CGNH) for precisely assessing trace-level SAPs. The AuNBP@PtPd-MoS2 nanozyme, via its stereoconfiguration and trimetallic synergy, recapitulates the dual enzyme-mimicking activities of GOx/CAT. Hence, it enables self-sustained interfacial charge transfer. As a signal probe, it efficiently accelerates self-cascade catalysis and electrochemical mass transfer. Additionally, CGNH creates an ideal interface for SAPs enrichment and cascade catalysis, featuring a hierarchical pore structure, a hybrid conductive network, and suitable biocompatibility. With self-assembled antifouling peptide nanoparticles (APNP) as a shielding barrier, the platform reliably detects SAPs in intricate biological matrices verified using cellular, murine and clinical specimens. Compared with conventional biomarkers, SAPs produce more informative readouts on disease progression. This electrochemical platform differentiates between benign and malignant breast diseases and healthy controls with high diagnostic accuracy (AUC = 0.962), especially for gray-zone differentiation and metastasis forecasting. This study offers new avenues for SAPs-based liquid biopsy to identify signs of breast cancer metastasis and is expected to become a reliable non-invasive tool for personalized breast cancer management.