A pH‑responsive hydrogel delivering ISOC1 modRNA attenuates disc degeneration by promoting BIRC6‑mediated MYC...

Intervertebral disc degeneration (IDD), a principal cause of chronic low back pain, is characterized by nucleus pulposus cell (NPC) apoptosis and currently lacks effective therapies. Through integrated multi-omics and Mendelian randomization analyses, we identified isochorismatase domain-containing 1 (ISOC1) as a key therapeutic target. To achieve controlled, context-specific expression within the acidic disc microenvironment, we designed an injectable, pH-responsive polyvinyl alcohol-phenylboronic acid-functionalized chitosan (PVA-csPBA) hydrogel for delivery of modified ISOC1 mRNA (modRNA). Mechanistically, ISOC1 promotes BIRC6-mediated ubiquitination and proteasomal degradation of MYC, thereby suppressing its transcriptional target SBSN. Suppression of the MYC/SBSN pathway directly ameliorates lactate-induced mitochondrial dysfunction and apoptosis in NPCs, preserving cellular viability and extracellular matrix homeostasis. In a rat IDD model, localized delivery of PVA-csPBA@ISOC1 modRNA effectively maintained disc hydration, mitigated nucleus pulposus tissue degeneration, and reduced annulus fibrosus fibrosis without observable systemic adverse effects. In summary, this work not only validates ISOC1 as a druggable target and elucidates its protective mechanism via inhibition of the MYC/SBSN pathway, but also establishes pH-responsive hydrogel-based modRNA delivery as a potent and precise regenerative strategy for counteracting IDD progression.