Ag-, Au-, Cu-, and Zn-based nanomaterials for bone regeneration: Materials design, biological mechanisms, and therapeutic applications

Bone defects resulting from trauma, tumors, and various pathological conditions pose significant clinical challenges owing to their complex healing dynamics and the limitations of conventional treatments, such as autografts and synthetic scaffolds. This review aims to comprehensively evaluate the role of metal-based nanomaterials in enhancing bone regeneration by elucidating their mechanisms of action and therapeutic potentials. Bone healing involves three main phases: inflammation, proliferation, and remodeling. Metal-based nanoparticles, such as silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), copper nanoparticles (CuNPs), and zinc nanoparticles (ZnNPs), actively support this process by enhancing bone formation (osteogenesis), promoting new blood vessel growth (angiogenesis), and providing antimicrobial effects to prevent infection. These nanoparticles exert multifaceted biological effects: AgNPs provide sustained antibacterial activity and modulate macrophage polarization to favor tissue repair; AuNPs regulate inflammation and stimulate osteogenic differentiation through pathways such as MAPK and Wnt/β-catenin, while also serving as drug delivery platforms; CuNPs enhance angiogenesis via HIF-1α and VEGF activation, support osteoblast proliferation, and balance inflammatory responses; ZnNPs reduce excessive inflammation and neutrophil extracellular trap (NET) formation, promote M2 macrophage polarization, and directly stimulate bone mineralization. The integration of these metal-based nanomaterials into scaffolds and delivery systems enables controlled ion release and improves biocompatibility, collectively advancing bone tissue engineering strategies. The complementary properties of Ag-, Au-, Cu-, and Zn-based nanomaterials address distinct challenges in bone defect management, including infection, insufficient vascularization, dysregulated inflammation, and impaired osteogenesis. This review consolidates current insights to inform future research directions and facilitate the clinical translation of metal-based nanotechnology for effective bone regeneration.