Hydrophobic Microenvironment Engineering of Single‐Atom Nanozymes for Proteolysis‐Driven Marine Antifouling

Peptide bond hydrolysis is essential to biology, yet the kinetic stability of amide bonds makes efficient and selective artificial proteolysis challenging. Here, we report a biomimetic Cu single‐atom nanozyme, Cu‐NC HSA, that integrates mixed d 9 ‐d 10 Cu‐N 4 active sites with a hydrogen‐substituted graphdiyne overlayer for selective protein hydrolysis. Mechanistic studies indicate that the Cu centers provide balanced Lewis acidity for carbonyl polarization and water activation, while the hydrophobic H‐GDY microenvironment preferentially enriches substrates bearing nonpolar residues. Under mild conditions (25°C, pH 6.0–10.0), Cu‐NC HSA hydrolyzes bovine serum albumin with a marked preference for peptide bonds adjacent to hydrophobic residues (86%). Beyond catalysis, Cu‐NC HSA shows potent antibiofilm activity, achieving biofilm removal in vitro and enabling sustained marine antifouling performance in a real marine environment. This work offers a multiscale biomimetic strategy for selective protein hydrolysis and marine antifouling applications.