Hyaluronidase-Responsive Composite Based on a Ligand-Engineered Ag(I) Complex with Enhancement in Released Ag+ for Targeted Antimicrobial Therapy

The potential clinical application of silver complexes as resistance-evading antibiotic alternatives for antimicrobial therapy is hindered by their unsatisfactory and uncontrolled Ag+ release, which often causes poor antibacterial efficacy or potential cytotoxicity. To address this limitation, we correlate a ligand engineering strategy to released Ag+ and develop a AgC≡CtBu-based complex (1) by facile exclusion of the N-donor bridging ligand. This structural modulation achieves higher intrinsic silver content (56.48%) with a Ag+ release ratio of 51.17%. Consequently, the same mass of 1 exhibits a boosted Ag+ release of 28.90 mg/L, significantly higher than that of 23.50 mg/L for the complex using the N-donor ligand. 1 exhibits stronger antibacterial activity with a far lower MIC value (3.24 × 10-4 mol Ag/L) than that of the above referenced complex (5.54 × 10-4 mol Ag/L) against Pseudomonas aeruginosa and carbapenem-resistant Escherichia coli. The correlation among coordination structure, Ag+ content, Ag+ release ratio, and antimicrobial activity is established using single crystal X-ray diffraction, atomic absorption spectroscopy, and various antimicrobial analyses. The sophistication of the ligand engineering strategy lies in the removal of the N-donor bridging ligand, which reduces the nuclearity of 1 as an Ag9 cluster ribbon with higher silver content, without compromising Ag+ release. Despite its elevated released Ag+, 1 demonstrates good biocompatibility at concentrations up to 64 mg/L. Further decorating 1 with hyaluronic acid (HA) yields a responsive composite 1@HA. HA coating effectively limits premature Ag+ release to 13.54% under physiological conditions and promotes Ag+ release to 47.18% upon 0.1 wt % hyaluronidase (HAase) exposure. Under the simulated infection, 1@HA exhibits HAase-responsive antibacterial behavior with larger inhibition zones and lower MICs than under noninfection conditions. 1@HA at 32 mg/L can achieve complete carbapenem-resistant Escherichia coli and Pseudomonas aeruginosa killing within 2 h. By decorating the Ag(I) complex featuring higher released Ag+ with HAase-responsive coating, this study provides an effective ligand design approach for enhanced and targeted antimicrobial efficacy.