Injectable ECM-mimetic hydrogels enable coordinated mitochondrial rejuvenation of senescent nucleus pulposus cells for repairing degenerative intervertebral discs

Mitochondrial dysfunction of nucleus pulposus cells (NPCs) drives IDD. • An injectable liposome-anchored ECM-mimetic hydrogel (ILH) is developed. • ILH repairs NPC mitochondria via SIRT1-AMPK-PGC-1α activation and ROS scavenging. • ILH reverses NPC senescence to restore disc structure and function. Mitochondrial dysfunction is a key driver of nucleus pulposus cell (NPC) senescence with crucial roles in orchestrating intervertebral disc (IVD) degeneration. However, the development of effective therapies is limited by the complex IVD structure and mitochondrial pathology. Here, an injectable liposome-anchored extracellular matrix (ECM)-mimetic hydrogel (ILH) was engineered for treating IVD degeneration via restoring mitochondrial biogenesis in senescent NPCs. Specifically, nicotinamide mononucleotide (NMN)-loaded liposomes were functionalized with the mitochondria-targeting peptide SS31 (MTLs) and incorporated together with Vitamin K 2 (VK 2 ) into an injectable hyaluronic acid-gelatin hydrogel crosslinked via dynamic Schiff base and boronate ester bonds. ILHs provide immediate mechanical support to degenerative IVDs while enabling on-demand release of encapsulated MTLs and VK 2 within the nucleus pulposus (NP). MTLs facilitates mitochondrial targeted-NMN delivery to replenish intracellular NAD + levels and activate SIRT1 signaling in senescent NPCs, thereby promoting AMPK-dependent mitochondrial biogenesis and suppressing the p53-associated senescence programs. On the other hand, SS31 alleviates cardiolipin peroxidation and preserves mitochondrial cristae integrity, while VK 2 activates the antioxidative Nrf2/HO-1 pathway to further improve mitochondrial quality control. Collectively, these coordinated effects enable comprehensive mitochondrial repair while further maintaining their structural and functional integrity in senescent NPCs, providing a promising therapeutic strategy for clinical treatment of IVD degeneration.