A nucleic acid regulation strategy under mechanical stress for intervertebral disc degeneration treatment

The nucleus pulposus (NP), the core shock-absorbing component of the intervertebral disc (IVD), plays a vital role in the pathogenesis of intervertebral disc degeneration (IVDD). Here, we uncover that degenerative NP tissue under mechanical stress is characterized by upregulated PIEZO1 and accumulation of cell-free DNA (cfDNA). Specific inhibition or knockout of PIEZO1 suppresses the cfDNA-induced NP degeneration. Mechanistically, PIEZO1-mediated calcium overload triggers mitochondrial DNA (mtDNA) leakage, initiating a cascade that culminates in MAFB-dependent activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome pathway. Targeting the PIEZO1-cfDNA-MAFB-NLRP3 axis, we developed a hydrogel nano composite system (HA-F127@MCC950 SiNPs) containing amino-functionalized SiO 2 nanoparticles (SiNPs) loaded with pyroptosis antagonist MCC950, embedded within hyaluronic acid (HA) and pluronic F127 (F127). The engineered hydrogel possesses dual effects in cfDNA scavenging and NLRP3 suppression in NP cells (NPCs). Moreover, this approach markedly attenuated NP degeneration progression in rat models of cfDNA-induced and temporary compression model (TCM)-induced IVDD. Collectively, this nucleic acid clearance strategy provides new insights for IVDD treatment.