Jie Li, Yang Zhang, Yi Liu, Yanjie Xu, Hui Xu, Qiangjun Ling, Zhen Tian, Chen Ling, Ziyang Tang, Kiram Abdukahar, Yang Yang Li, Zongshan Hu, Yong Qiu, Liming Bian, Zezhang Zhu, Kunyu Zhang, Zhen Liu
In osteoporotic fracture-related infection (FRI), the coordinated bone healing is compromised by cortical bone lysis and persistent bacterial colonization. Current treatments primarily focus on infection control, but fail to preserve bone microarchitecture or restore disrupted healing cascade, particularly in fragile osteoporotic bone. Here, we develop a bioactive nanocomposite hydrogel based on bisphosphonate-modified hyaluronan (HABP) and either free bisphosphonate (BP) or pyrophosphate (TSPP), carrying antibacterial Ag⁺ ions and Vancomycin. Triggered by the pathological pH of biofilms, this hydrogel enables site-specific release of antimicrobials. In a rat osteoporotic FRI model, prominent cortical bone lysis and osteocyte apoptosis impair healing. HABP hydrogel effectively eradicates the Methicillin-resistant Staphylococcus aureus infection, preserves cortical bone integrity, and rescues osteocyte viability by inhibiting osteoclast activation and osteocyte apoptosis. The TSPP-based formulation, delivering a lower BP dose, enhances callus remodeling. Our study demonstrates the promising potential of the dual-action hydrogel for treating osteoporotic FRI via preventing bone lysis and rejuvenating coordinated healing cascades. In osteoporotic fracture-related infection (FRI), coordinated bone healing is compromised by cortical bone lysis and persistent bacterial colonization. Here, Li et al. report a dual-action nanocomposite bisphosphonates hydrogel for treatment of osteoporotic FRI that preserves cortical bone integrity and restores fracture healing.