Rejuvenation Modulation of Nucleus Pulposus Progenitor Cells Reverses Senescence‐Associated Intervertebral Disc Degeneration

Abstract The decreased regeneration potential of aging nucleus pulposus resident progenitor cells (NPPCs) fails to resist intervertebral disc degeneration (IVDD), and strategies to remodel the regeneration capacity of senescent NPPC are urgently needed. A decrease in Klotho gene expression in NPPCs of both old mice and humans exacerbates the impaired regenerative functionality of NPPC. Here, an NPPC‐targeted lipid thymine nanoparticle (NT‐LNP) 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‐house 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‐LNPs 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‐engineered to be youthful and pluripotent to maintain homeostasis and rejuvenation, thereby providing a reversible treatment strategy for IVDD with broad application in other senescence‐related diseases.