Nanoparticle-mediated bone regeneration: From molecular mechanisms to clinical translation.

Reconstruction of critical-size bone defects remains a persistent clinical challenge after trauma, tumour resection and degenerative disease. Nanoparticles (NPs) have emerged as versatile platforms that couple tunable material properties with targeted molecular delivery to direct regeneration. This review synthesizes advances from the past decade across inorganic (for example, nanostructured hydroxyapatite and bioactive glasses), polymeric, lipid, and bioinspired NPs, and links key design parameters-size, shape, mechanics, surface chemistry and degradability-to osteogenic outcomes. We examine how NPs steer stem-cell fate through mechanotransduction and canonical signaling (Wnt/β-catenin, BMP/Smad, MAPK), and highlight emerging mechanisms including controlled ion release, redox modulation, protein-corona dynamics and macrophage immune reprogramming toward pro-healing phenotypes. Three key modes of translational application are emphasized: NPs as carriers for proteins, nucleic acids and small molecules; as bioactive or reinforcing components within load-bearing scaffolds; and as injectable microenvironments that provide spatiotemporal control of cell signaling cues. Ongoing clinical applications in dental, orthopedic and spinal therapeutics show growing adoption, while also revealing gaps in long-term safety, Good Manufacturing Practices (GMP), and regulation. In future developments, stimuli-responsive and self-reporting nanomaterials, informed by AI-guided design and integrated with 3D bioprinting, offer routes to patient-specific grafts with predictable performance. By consolidating mechanisms into practical design rules, we chart a path from tunable nanoscale interfaces to reliable, clinically impactful bone regeneration.