Bioengineered hollow nanoflowers to synergistically modulate inflammation, angiogenesis and osteogenesis for enhancing repair of bone defects

Abstract

Background: Inadequate control of inflammation and insufficient vascularization remain major challenges in repair of bone defects. Here, we developed a multifunctional nanoflower, Au NPs@ZIF-8/Ga, by loading gallic acid (Ga) into a nanoflower-like structure consisting of gold nanoparticles (Au NPs) core and zeolitic imidazolate framework-8 (ZIF-8) shell, to synergistically exert anti-inflammatory, pro-angiogenic, and osteogenic effects. Results: The hollow architectures of the synthesized Au NPs@ZIF-8/Ga nanoflowers were characterized by transmission electron microscopy (TEM), energy-dispersive spectroscopy (EDS), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and nitrogen adsorption–desorption analysis. In vitro studies demonstrated that Au NPs@ZIF-8/Ga reduced secretion of pro-inflammatory cytokines in macrophages via suppressing NF-κB pathway activation, while concurrently promoted endothelial cell migration, and tube formation. Yet, Au NPs@ZIF-8/Ga enhanced osteogenic differentiation of MC3T3-E1 cells, as evidenced by the upregulated expression of bone formation related genes runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN), as well as increased alkaline phosphatase (ALP) activity and bone matrix mineralization. In vivo studies showed that Au NPs@ZIF-8/Ga promoted early resolution of inflammation, neovascularization and robust new bone formation in a rat model with critical-sized calvarial defects, as confirmed by Micro-computed tomography (micro-CT) and histological analyses. Conclusion: Collectively, this work presents a versatile nanoplatform for reducing inflammation in early stage while subsequently promoting angiogenesis and osteogenesis, thereby offering a promising therapeutic strategy for bone regeneration under inflammatory conditions.