Hypoxic-inflammatory preconditioning endows BMSC-derived appoptotic extracellular vesicles with potent efficacy against IVDD via cell activation and mitochondrial homeostasis regulation.

Intervertebral disc degeneration (IVDD) is the primary cause of chronic low back pain, with the senescence of nucleus pulposus cells (NPCs) as its core driving mechanism. Mitochondrial homeostasis acts as a critical mediator linking cellular stress responses to the senescence program of nucleus pulposus cells. Recent studies have indicated that the transplantation of apoptotic extracellular vesicles (ApoEVs) derived from the apoptotic mesenchymal stem cells (MSCs) represents a novel direction for tissue regeneration therapy. Given that the pathological microenvironment of IVDD exhibits hypoxic-inflammatory characteristics, the functional regulatory effects of ApoEVs pretreated under such conditions remain unclear. Here, we aimed to assess whether modulation of the MSCs culture microenvironment (hypoxia alone versus hypoxic-inflammatory conditions) generates ApoEVs (specifically I-ApoEVs) with enhanced therapeutic efficacy in the context of IVDD repair. A secondary focus of this study was to clarify the underlying mechanism through which such therapeutic effects are mediated by the regulation of mitochondrial homeostasis. Notably, the results demonstrated that I-ApoEVs were significantly superior to enhance the viability of NPCs and improve mitochondrial function. These findings suggest that the combined hypoxic-inflammatory pretreatment can more efficiently enhance the capacity of MSCs-derived ApoEVs to regulate mitochondrial homeostasis, thereby providing experimental evidence for optimizing ApoEV-based therapeutic strategies for IVDD.