Peptide Receptor‐Functionalized AuNP‐Embedded Zwitterionic Biopolymeric Nanohydrogel for Electrochemical Sclerostin Sensing

ABSTRACT Sclerostin (SOST) is a key negative regulator of bone formation and an emerging biomarker associated not only with osteoporosis but also with chronic kidney disease. Despite its growing clinical relevance, biosensing platforms for SOST remain limited, with most existing approaches relying on antibody‐ or aptamer‐based assays that often suffer from high cost, limited stability, and reduced performance in complex biological samples. Here, we report a peptide‐based electrochemical biosensing platform enabled by a multifunctional zwitterionic biopolymeric nanohydrogel, composed of chitosan, carboxybetaine methacrylate, and gold nanoparticles (CS–ZI–AuNPs). This nanohydrogel acts as a unified antifouling biointerface, simultaneously providing resistance to nonspecific adsorption, stable peptide receptor immobilization, and efficient electrochemical signal transduction. The resulting biosensor achieves picomolar sensitivity with a detection limit of approximately 26.4 pg/mL, enabling accurate quantification of SOST across clinically relevant concentration ranges. Importantly, the platform demonstrates statistically significant discrimination between healthy individuals and patients with osteoporosis, postmenopausal osteoporosis, and chronic kidney disease (stages 1 and 3) using real clinical samples. By integrating zwitterionic antifouling chemistry with peptide‐driven molecular recognition in a conductive nanostructured matrix, this work establishes a generalizable design principle for electrochemical biosensors targeting protein biomarkers. The proposed strategy offers a robust and scalable alternative to conventional immunoassays, with broad implications for translational diagnostics and real‐time disease monitoring.