Fluorinated Side-Chain-Modified Peptides Inspired by Shark Skin for Antifouling Electrochemical Biosensing: Ultrasensitive Detection of CA15–3 in Human Saliva

A major challenge limiting the practical application of electrochemical biosensors is biofouling in complex biological environments, leading to poor signal strength, reduced operational stability, and thereby impaired practical utility. One promising solution lies in the rational design of well-structured and highly functional antifouling coatings. Inspired by the antifouling synergy between the superhydrophilic dermal denticles and the low-surface-energy mucus layer of shark skin, we engineered a biomimetic fluorinated side-chain-modified peptide (FSP) by developing hydrophilic zwitterionic peptides with grafted low-surface-energy fluorinated alkyl chains. Leveraging this material, we constructed an antifouling electrochemical biosensor, which was capable of ultrasensitive detection of CA15-3 in human saliva. The hydrophilic segment of the FSP forms a dense hydrated layer with water molecules to repel contaminants, while its fluorinated side chains reduce interfacial adhesion due to their extremely low surface energy. This synergistic effect endows the FSP with superior antifouling performance compared to conventional zwitterionic peptides (ZIP). The FSP-based biosensor enabled highly sensitive detection of CA15-3 in human saliva across a broad linear range of 0.01 to 1000 U·mL^-1 with a limit of detection as low as 2.85 mU·mL^-1, while showing consistent results with ELISA in authentic samples. The biomimetic peptide design strategy with hydrophilic and low-surface-energy synergy offers a valuable framework for the design of next-generation electrochemical biosensors with enhanced robustness and powerful antifouling performance.