Metallothionein‐Inspired Dual‐Stage Ion‐Regulatory Coatings With Infection‐Triggered Bactericidal Activity and Long‐Term Antifouling Protection

Abstract

ABSTRACT The long‐term failure of implantable stents originates from static protection that cannot adapt to the temporal shift of primary risks from early‐stage infection and late‐stage biofilm–mineral occlusion. Inspired by the dynamic metal homeostasis of metallothioneins, we propose a β ‐hydroxy thioether–based ion‐regulatory network that programs competing binding sites with distinct kinetic and thermodynamic preferences, thereby embedding an intrinsic functional clock into an otherwise static material. As a proof of concept, silver is employed as a representative ion to demonstrate how conventional metal bactericides can be transformed into stage‐adaptive defense factors. Initially, the system is dominated by labile hydroxyl complexation, triggering silver ion release under infection‐associated acidification and enabling rapid bactericidal clearance. Over time, the system shifts toward thermodynamically favored thioether coordination, which becomes dominant and reprograms the coating, resulting in bacterial repulsion and mineral exclusion at sub‐bactericidal ion levels. The stage‐adaptive protection is validated in methicillin‐resistant Staphylococcus aureus ‐infected wound and long‐term (3‐month) bladder indwelling models. This work establishes time‐programmable ion regulation as an extensible design concept for adaptive biomaterials capable of coping with evolving biological environments.