Abstract: The pathological microenvironment of osteoporosis poses a substantial clinical challenge for bone defect regeneration. Through single-cell RNA-sequencing (scRNA-seq) analysis, we identified a reactive oxygen species (ROS)-overloading osteoblast subpopulation as a critical pathological feature of osteoporotic niches. Guided by scRNA-seq analysis, we engineered a microenvironment-adaptive hydrogel system through precise integration of antioxidant curcumin-encapsulated zeolitic imidazolate framework-8 nanoparticles (CCM@ZIF-8 NPs) within photo-crosslinkable alginate methacrylate (AlgMA) hydrogel (AlgMA/CCM@ZIF-8). This engineered design exhibited dual functions: effectively scavenging ROS in bone marrow-derived mesenchymal stem cells (BMSCs) while simultaneously suppressing osteoclast differentiation. The osteo-regenerative superiority of the AlgMA/CCM@ZIF-8 nanocomposite hydrogel was conclusively demonstrated in bone defect models of osteoporotic mice. This scRNA-seq-informed engineering strategy offers a promising approach for developing pathophysiology-adapted biomaterials to promote regenerative repair in osteoporotic bone defects.

Key words: Osteoporosis; Single-cell RNA-sequencing (scRNA-seq); Reactive oxygen species (ROS); Curcumin (CCM); Bone regeneration

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