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A decrease in Klotho gene expression in NPPCs of both old mice and humans exacerbates the impaired regenerative functionality of NPPC. Here, an NPPC\u2010targeted lipid thymine nanoparticle (NT\u2010LNP) is reported for the in situ manipulation of the regenerative repair potential of NPPCs, restoration of degenerated nucleus pulposus tissue, and mitigation of IVDD. Specifically, the results showed that the in\u2010house customized lipid nanoparticles efficiently introduced Klotho circular ribonucleic acid (circRNA) into NPPCs to engender a renascent phenotype and tuned the balance of extracellular matrix synthesis\/catabolism in vitro and in vivo. Moreover, an intradiscal injectable hydrogel system that scavenges chemokines (MCP1 and IL8) in tandem with NPPCs rejuvenated NT\u2010LNPs in the IVD, modulating the inflammatory environment and synergistically promoting the regeneration of degenerated intervertebral discs. In summary, the findings establish that NPPCs can be re\u2010engineered to be youthful and pluripotent to maintain homeostasis and rejuvenation, thereby providing a reversible treatment strategy for IVDD with broad application in other senescence\u2010related diseases.<\/jats:p>","DOI":"10.1002\/adma.202409979","type":"journal-article","created":{"date-parts":[[2024,12,29]],"date-time":"2024-12-29T23:00:21Z","timestamp":1735513221000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Rejuvenation Modulation of Nucleus Pulposus Progenitor Cells Reverses Senescence\u2010Associated Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"37","author":[{"given":"Da\u2010wang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Orthopedics Qilu Hospital Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Department of Pharmaceutics School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  44 Cultural West Road Jinan Shandong 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Qilu Hospital Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Department of Pharmaceutics School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  44 Cultural West Road Jinan Shandong 250012 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