Tri-Functional MgTA@MnO2 Nanozymes Orchestrate Redox Defense, Angiogenesis, and Immunometabolism for Osteoporotic Bone Regeneration

Purpose: In osteoporotic conditions, bone regeneration is hindered by a pathological triad: persistent oxidative stress, compromised vascularization, and a dysregulated osteoimmune microenvironment. The purpose of this study was to engineer a multifunctional nanotherapeutic platform capable of orchestrating redox defense, angiogenesis, and immunometabolic reprogramming to accelerate bone repair. Methods: We synthesized a tri-functional nanozyme (MgTA@MnO 2 ) featuring a metal-phenolic network (MPN) coating, established through the one-step coordination of tannic acid (TA) and magnesium ions (Mg 2 ⁺) onto manganese dioxide nanoparticles. For sustained local delivery, these catalytic nanomedicines were dispersed within a standard photocrosslinkable, injectable methacrylated gelatin (GelMA) matrix. The system’s efficacy was evaluated across pre-osteoblast, endothelial, and macrophage cell models. Underlying immunomodulatory mechanisms were delineated using transcriptomic sequencing. Therapeutic outcomes were assessed in an ovariectomized (OVX) osteoporotic rat model bearing femoral bone defects. Results: The localized nanozyme delivery system efficiently scavenged reactive oxygen species (ROS), protecting osteoblasts from oxidative damage by awakening the endogenous NRF2 defense pathway. The platform also robustly stimulated endothelial cell migration and tube formation. Crucially, Mg 2 ⁺ and TA synergized with the MnO 2 core to drive precise macrophage reprogramming, shifting the population from a pro-inflammatory M1 state toward a pro-reparative M2 phenotype. Transcriptomic profiling revealed this immunometabolic transition was dictated by targeted suppression of the IL-17/MAPK/NF-κB inflammatory axis and concurrent activation of the STAT3/IL-10 cascade. Consequently, this optimized osteoimmune niche promoted osteogenesis while restraining osteoclastogenesis in vitro. In vivo evaluations confirmed excellent biosafety and demonstrated markedly accelerated, vascularized trabecular bone regeneration, correlating with robust M2 macrophage infiltration. Conclusion: By coupling catalytic ROS scavenging with targeted immunometabolic modulation, the MgTA@MnO 2 nanotherapeutic system successfully remodels the hostile osteoporotic microenvironment. Utilizing a conventional hydrogel as a local vehicle, this tri-functional nanozyme approach provides a highly translatable paradigm for managing compromised bone fractures. Keywords: nanomedicine, osteoimmunomodulation, macrophage polarization, metal-phenolic network, magnesium ion delivery, osteoporotic fracture healing