Precursor-Encoded Metal-Free Carbon Dots Reshape the Bone-Regenerative Microenvironment: Materials Chemistry, Multiscale Mechanisms, and a Translational Roadmap.

Abstract

Bone-defect healing is a spatiotemporally coordinated continuum involving inflammatory initiation and resolution, redox re-equilibration, immune-cell state transitions, angiogenesis, osteogenic commitment of mesenchymal stromal/progenitor cells, and osteoblast-osteoclast coupling. Although metal-containing nanomaterials can enhance regeneration through ion release, catalysis, or photothermal effects, their performance is often constrained by local dose, oxidation state, release kinetics, and long-term accumulation. Metal-free carbon dots (CDs) combine nanoscale interfacial activity, programmable surface chemistry, electron-transfer capacity, intrinsic fluorescence, and scaffold compatibility and are consequently evolving from imaging probes into bioactive regulators of the bone-repair microenvironment. Following the sequence of precursor chemistry-carbonization reconstruction-surface state-protein corona/organelle response-tissue regeneration, this review compares CDs derived from citric acid, ascorbic acid, amino acids, curcumin, artesunate, yam, clove, ginger, and other natural or medicinal-food precursors. We critically examine context-dependent redox regulation, macrophage-state remodeling, osteogenic and epigenetic control, suppression of pathological osteoclastogenesis, infection control, and angiogenesis-osteogenesis coupling. Current evidence is limited by ambiguous structural identity, confounded activity attribution, correlation-dominant mechanisms, overextension from simplified models, and insufficient long-term safety assessment. Translation will require fractionation-based identity definition, multi-batch potency assays, target-protein capture, organelle tracking, genetic rescue, spatial omics, and quantitative integration of chemistry, local exposure, degradation/clearance, and regenerative efficacy. Particular attention is given to how CD surface states interact with collagen, fibrin, and glycosaminoglycan matrices to govern protein adsorption, local retention, matrix organization, and growth-factor presentation. A two-tier evidence roadmap is proposed, prioritizing fraction-resolved activity attribution, compartment-specific redox assays, post-formulation identity testing, and context-matched progression from screening defects to load-bearing and comorbidity models.