ROS-responsive hydrogel microspheres deliver shTMEM2-loaded liposomes to suppress pyroptosis and ameliorate intervertebral disc degeneration.

Low back pain (LBP) is a highly prevalent musculoskeletal disorder worldwide. Nucleus pulposus cell (NPC) pyroptosis contributes to intervertebral disc degeneration (IVDD), but the underlying mechanisms remain unclear. We identified TMEM2, a transmembrane protein not previously linked to IVDD, as markedly upregulated in degenerated NPCs by single‑cell RNA sequencing. TMEM2 expression correlated positively with IVDD severity and NPC pyroptosis, and its knockdown alleviated pyroptosis. Mechanistically, TMEM2 binds BAX to promote mPTP opening, leading to mtDNA release and activation of the STING-TBK1-NF‑κB pathway, ultimately triggering NLRP3 inflammasome‑mediated pyroptosis. To address the avascular nature of the disc, we developed an injectable ROS‑responsive hydrogel microsphere system encapsulating shTMEM2‑loaded liposomes (Lipo/shTMEM2@MS). This platform enables sustained release, on‑demand degradation, and single‑dose intradiscal administration. In a rat model, Lipo/shTMEM2@MS effectively ameliorated disc degeneration. Collectively, these findings identify TMEM2 as a key driver of NPC pyroptosis and establish a ROS‑responsive microsphere strategy as a promising translational approach for IVDD.