pH‐Responsive Psoralen Delivery System for Infected Bone Defects: Spatiotemporal Photothermal Disinfection Coupled with Osteogenesis and Osteoclast Regulation

ABSTRACT The treatment of infected bone defects remains a significant clinical challenge, necessitating rigorous infection control alongside effective bone reconstruction. To address this, we develop a pH‐responsive, zeolitic imidazolate framework‐8 (ZIF‐8)‐based delivery system for targeted psoralen (PSO) delivery, which provides dual functionalities: antibacterial activity and osteogenic modulation. These nanoparticles (NPs) are further functionalized with a polydopamine (PDA) coating, designated as PSO/ZIF‐8@PDA NPs (PZP NPs), to achieve synergistically enhanced therapeutic efficacy through photothermal activity. Exploiting rapid degradation in the acidic microenvironment of infected bone defects and slow degradation in the neutral microenvironment, these PZP NPs undergo spatiotemporal transformation, enabling sequential antibacterial and osteogenic modulation at the defect sites through the concentration‐dependent effects of PSO. In vitro optimisation of PSO loading establishes a balance between osteogenic potency, antimicrobial efficacy, and biocompatibility, defining an optimal therapeutic platform for nanocarrier performance. In vivo evaluation in polymicrobial ( Staphylococcus aureus and Escherichia coli )‐infected rat calvarial defect models demonstrates effective pathogen eradication and enhanced osteogenic differentiation. This dual‐functional nanoplatform represents a promising strategy for the clinical management of infected bone defects and broadens the potential of nanomedicine in regenerative applications for infected tissues.