A pH‑responsive hydrogel delivering ISOC1 modRNA attenuates disc degeneration by promoting BIRC6‑mediated MYC degradation and inhibiting SBSN expression

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. Schematic representation of pH-responsive hydrogel-mediated ISOC1 modRNA delivery for the treatment of intervertebral disc degeneration (IDD). Through integrated multi-omics analysis combining single-cell RNA sequencing, bulk transcriptomics, and Mendelian randomization, ISOC1 was identified as a key therapeutic target in IDD. A pH-responsive hydrogel was engineered by cross-linking polyvinyl alcohol (PVA) with phenylboronic acid-functionalized chitosan (csPBA) to encapsulate ISOC1 modRNA. The resulting PVA–csPBA@ISOC1 modRNA hydrogel exhibits injectability, self-healing properties, and accelerated cargo release under the acidic conditions characteristic of the degenerative disc microenvironment. Mechanistically, ISOC1 suppresses suprabasin (SBSN) expression by promoting BIRC6-mediated ubiquitination and proteasomal degradation of MYC, thereby mitigating lactate-induced apoptosis and preserving mitochondrial function in nucleus pulposus cells (NPCs). In vivo, intradiscal injection of PVA–csPBA@ISOC1 modRNA maintains disc hydration, prevents nucleus pulposus tissue loss, and attenuates annulus fibrosus fibrosis without detectable systemic toxicity.