Cascade Dual‐Stimuli‐Responsive Antimicrobial Composites Based on Hyaluronic Acid‐Coated pH‐Sensitive Ag(I) Complexes as Targeted Bactericide

We designed two intelligent composites based on hyaluronic acid (HA) coated Ag(I) complexes with cascade dual‐stimuli‐responsive Ag + release to tackle the escalating threat of drug resistance while minimizing the off‐target toxicity originating from the always‐on Ag + release and degradation of an additional carrier. The Ag(I) complexes assembled with pH‐sensitive coordination bonds (Ag–N in 1 and Ag–S in 2 ) integrate antimicrobial activity, carrier function, and acid response, offering a new design logic for an antibiotic‐free, carrier‐free, and resistance‐targeting bactericide. HA coating further functions as a hyaluronidase‐responsive gatekeeper, suppressing the premature Ag + release under physiological conditions and promoting Ag + release upon hyaluronidase stimulation. Cascade dual‐stimuli‐responsive is integrated by hyaluronidase‐triggered degradation of HA coating, followed by acid‐induced cleavage of coordination bonds, leading to Ag + release from exposed Ag(I) complexes. The resulting dual‐stimuli‐responsive Ag + release ratios (44.13% for 1 @HA and 56.09% for 2 @HA) exceeded those of each individual stimulus and their theoretical additive sums. Under simulated dual stimuli, minimum inhibitory concentrations of the composites decreased to 16 mg/L against Pseudomonas aeruginosa and carbapenem‐resistant Escherichia coli . Correlation of crystal structure, Ag + release, and antimicrobial activity further elucidated that the antimicrobial efficacy of Ag(I) complexes was governed not only by Ag + release but also by their ligand‐exchange capability with biological ligands at bacterial targets. By facilely integrating enzymatic targeting and pH‐amplified Ag + release into a single system, this work successfully establishes an antibiotic‐free antimicrobial platform translating infection signals into targeted therapeutic actions.