Amelioration of intervertebral disc degeneration using engineered extracellular vesicle-delivered ZDHHC5 via inhibiting PANoptosis

Intervertebral disc degeneration (IDD) is a common condition and a leading cause of chronic low back pain, affecting millions of individuals worldwide. Human Umbilical Cord Mesenchymal Stromal Cell (hUCMSC)-derived extracellular vesicles (EVs) are emerging as a promising therapeutic strategy for IDD. However, the limited production yield and unclear mechanisms by which EV contents mediate their therapeutic effects have hindered the clinical application of EVs. In this study, using transcriptomic data and single-cell RNA sequencing, we identify PANoptosis as a key mechanism driving the progression of IDD. Furthermore, parathyroid hormone (PTH) enhances the secretion of hUCMSC-derived EVs and alters their cargo composition, which may contribute to their improved therapeutic effects. Mechanistically, PTH-preconditioned EVs, enriched with ZDHHC5, ameliorate PANoptosis by modulating ZBP1 transcription through competitive inhibition of YBX1 phosphorylation via palmitoylation. Our findings provide strong support for a cell-free therapeutic strategy utilizing EVs from PTH-preconditioned MSCs for IDD treatment and propose the ZDHHC5/YBX1/ZBP1 axis as a novel molecular target for inhibiting PANoptosis, thus paving the way for clinical translation and broader healthcare applications.