Immune-activating PTL/nanowire composite coating on Ti surface enables macrophage-driven bacterial clearance and osseointegration

Implant-associated infections and loosening remain formidable clinical challenges. Conventional strategies such as incorporating antibiotics and metal ions can result in drug resistance and systemic toxicity, ultimately compromising tissue regeneration. Herein, we propose an immune-driven strategy for safe and effective anti-infection and pro-osseointegration, in which early immune activation promotes bacterial clearance, followed by timely resolution of inflammation to support angiogenesis and osteogenesis. As proof of the principle, gradient phase-transited lysozyme (PTL) on fixed size sodium titanate nanowires (PTL/nanowire composite coating) was constructed on Ti surface, creating a multifunctional platform for high-throughput screening (HTS) of optimal PTL dosages to support macrophage-driven bacterial clearance and osseointegration. The results revealed that PTL markedly enhanced bacterial clearance of macrophages (MΦs) through activating their Toll-like receptor 4 (TLR4) signaling pathway, while the nanowires beneath the PTL could promptly convert MΦs into pro-healing M2 phenotype, creating favorable macrophage-mediated immune microenvironment that promoted angiogenesis and osteogenesis. Among the tested formulations, moderate PTL dosage (PTL-3) achieved optimal balance of bacterial clearance and bone regeneration. In vivo experiments further corroborated the efficacy of PTL/nanowire composite coating in promoting infectious bone regeneration. This study underscores the potential of PTL/nanowire composite coatings for safely and effectively macrophage-driven bacterial clearance and osseointegration, paving the way for clinical translation in orthopedic and dental applications. • PTL coatings activate macrophages via TLR4 to enhance bacterial clearance. • Moderate PTL dosage balances infection control with tissue regeneration. • Macrophage-driven antibacterial defense outperforms direct antibacterial activity. • PTL-3 coating creates optimal immune microenvironment for osseointegration. • Immune-activating strategy prevents implant infection without antibiotics.