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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\u2212carbonization reconstruction\u2212surface state\u2212protein corona\/organelle response\u2212tissue 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\u2212osteogenesis 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.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.6c01439","type":"journal-article","created":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T06:02:04Z","timestamp":1792821724000},"page":"6018-6032","source":"Crossref","is-referenced-by-count":0,"title":["Precursor-Encoded Metal-Free Carbon Dots Reshape the Bone-Regenerative Microenvironment: Materials Chemistry, Multiscale Mechanisms, and a Translational Roadmap"],"prefix":"10.1021","volume":"12","author":[{"given":"Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Binhai County People\u2019s Hospital , ,","place":["Jiangsu, China, 224500"]},{"name":"The Third People's Hospital of Qidong , , ,","place":["Qidong, China, 226200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai","family":"Liang","sequence":"additional","affiliation":[{"name":"Maternal and Child Health Hospital of Changxing County , ,","place":["Changxing, China, 313100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baisheng","family":"Cai","sequence":"additional","affiliation":[{"name":"Yangcheng Dafeng People\u2019s Hospital , ,","place":["Jiangsu, China, 224500"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0209-176X","authenticated-orcid":true,"given":"Su","family":"Jiang","sequence":"additional","affiliation":[{"name":"Binhai County People\u2019s Hospital , ,","place":["Jiangsu, China, 224500"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,24]]},"reference":[{"key":"2026110907075537600_cit1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41584-022-00887-0","article-title":"The decisive early phase of bone regeneration","volume":"19","author":"Duda","year":"2023","journal-title":"Nat. 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