{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:35:13Z","timestamp":1792694113367,"version":"4.5.0"},"reference-count":183,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, yet current clinical interventions remain largely palliative and fail to restore disc structure and function. While mesenchymal stem cells (MSCs), exosomes, and bioengineered scaffolds have emerged as promising regenerative tools, isolated therapeutic applications often fail to overcome the highly hostile IVDD microenvironment\u2014characterized by severe hypoxia, acidosis, and mechanical overload. This review provides a unique perspective by positioning the \u201ccell-material-molecule\u201d cross-integration as the central paradigm for effective disc regeneration. We critically synthesize how smart biomaterials are engineered to physically match and survive the degenerative niche, thereby providing a resilient sanctuary for MSCs. Concurrently, we highlight how engineered MSCs and their cell-free derivatives (exosomes and regulatory RNAs) synergistically dismantle inflammatory cascades and matrix breakdown. Beyond outlining preclinical and clinical advances, this review deeply analyzes persistent translational bottlenecks\u2014such as cell source standardization, large-scale GMP exosome manufacturing, and long-term scaffold biocompatibility. Ultimately, by outlining the convergence of gene editing, responsive biomaterials, and precision delivery, we define a clear roadmap for transitioning IVDD treatment from palliative symptom management to durable, precision regenerative medicine.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1802866","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:05:51Z","timestamp":1779689151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Rebuilding the degenerative disc microenvironment: mesenchymal stem cells, exosomes, and bioengineered scaffolds"],"prefix":"10.3389","volume":"14","author":[{"given":"Dong","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102569","DOI":"10.1016\/j.redox.2022.102569","article-title":"Silica nanoparticles aggravated the metabolic associated fatty liver disease through disturbed amino acid and lipid metabolisms-mediated oxidative stress","volume":"59","author":"Abulikemu","year":"2023","journal-title":"Redox Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"658","DOI":"10.3390\/ijms20030658","article-title":"NF-\u03baB-associated pain-related neuropeptide expression in patients with degenerative disc disease","volume":"20","author":"Ahmed","year":"2019","journal-title":"Int. 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