Dual‐Anchored Clickable Peptide via SPAAC for Gelatinase‐Responsive Antibacterial and Osteogenic Functions on Titanium Implants

ABSTRACT Antibacterial orthopedic implants that simultaneously promote osteointegration remain an unmet clinical challenge. Conventional enzyme‐responsive antibacterial surfaces often suffer from irreversible loss of osteogenic motifs upon activation, limiting their regenerative capacity post‐infection. Herein, we report a dual‐anchored peptide design engineered on titanium implants (Ti‐Dual) that addresses this limitation by retaining biofunctional motifs after pathogen‐triggered activation. The peptide construct integrates an antimicrobial sequence (HHC36) and a cell‐adhesive RGD motif connected via a gelatinase‐cleavable spacer (GPLGV). Terminal azide groups enable stable dual‐point grafting through SPAAC chemistry, overcoming the low grafting efficiency associated with mixed RGD grafting systems. Under physiological conditions, the constrained conformation suppresses antibacterial activity, favoring osteogenesis. Upon infection, bacterial gelatinase cleaves the linker, activating rapid and potent antibacterial effects—eliminating 99.37% of P. aeruginosa within 10 min, and 99.73% of S. aureus and 99.99% of P. aeruginosa within 120 min—while the RGD motif remains anchored, ensuring continuous cell adhesion and tissue integration. In vivo, Ti‐Dual effectively eradicated multidrug‐resistant P. aeruginosa , suppressed inflammatory responses, mitigated bone resorption, and enhanced osteogenesis in a rat femoral infection model. This design resolves the critical trade‐off between infection responsiveness and sustained pro‐regenerative function, offering a robust and adaptive strategy for infected bone defect repair.