ROS-responsive mitochondria-targeting nanocomposite reprograms the IRGM1–mitophagy axis to restore mitochondrial homeostasis and suppress pyroptosis in intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with complex pathological mechanisms and a principal cause of low back pain worldwide. Increasing evidence indicates that NLRP3-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a key role in IVDD progression. Meanwhile, mitophagy-mediated mitochondrial quality control has emerged as an important protective mechanism against inflammatory degeneration. However, the mechanisms linking mitophagy dysfunction to pyroptotic activation remain incompletely understood. Here, we identified immunity-related GTPase family M protein 1 (IRGM1) as a regulator of mitophagy in NPCs. IRGM1 deficiency impaired mitophagic activity, resulting in disrupted mitochondrial homeostasis, excessive ROS accumulation, and activation of NLRP3-mediated pyroptosis. Mechanistically, restoration of IRGM1 expression promoted PINK1/Parkin-mediated mitophagy, improved mitochondrial function, and suppressed pyroptotic signaling in degenerative NPCs. Through virtual screening and molecular validation, Diosmetin was identified as a potential IRGM1-regulating compound. To enhance therapeutic efficacy, we engineered a ROS-responsive mitochondria-targeting nanocomposite system (DPTGT) for localized and sustained Diosmetin delivery. Both in vitro and in vivo experiments demonstrated that DPTGT effectively restored IRGM1-mediated mitophagy, suppressed pyroptotic activation, and alleviated IVDD progression. Collectively, this study establishes the IRGM1–mitophagy axis as a critical regulatory mechanism in IVDD and provides a mechanism-guided nanotherapeutic strategy for disc degeneration intervention.