Multifunctional Biomimetic Trojan Horse Nanosystem for Remodeling Infected Regenerative Microenvironments in Osteoporotic Bone Defects.

Infection is the most common complication of osteoporotic fractures, often characterized by bacterial resistance and intracellular infection, posing a major challenge in the treatment of osteoporotic fractures. Here, we developed a multifunctional biomimetic Trojan horse nanosystem based on hydroxyapatite nanotubes (NT-HA) for microenvironment remodeling. The NT-HA exhibits a dual-stage antimicrobial peptide (AMP) delivery strategy, in which surface-adsorbed AMPs are rapidly released to eliminate extracellular bacteria, while NT-HA is internalized via endocytosis to release encapsulated AMPs for efficient intracellular bacterial clearance. After releasing AMPs, the NT-HA can regulate the PI3K-AKT signaling cascade, promoting the directed osteogenic differentiation of osteoporotic bone marrow mesenchymal stem cells (OBMSCs). In the repair of infected osteoporotic bone defects in vivo, this Trojan horse nanosystem not only enhances bone regeneration by eliminating cellular infections and inducing OBMSCs osteogenesis but also reduces peri-implant bone loss and strengthens bone strength, ultimately remodeling the regenerative microenvironment to achieve optimal bone defect repair and functional reconstruction.