A Dual-Functional Nanoplatform Targeting the dsDNA-cGAS Axis to Mitigate Disc Degeneration and Aberrant Innervation

Pathological sensory nerve ingrowth into degenerated intervertebral discs contributes to discogenic pain, yet strategies that concurrently mitigate disc degeneration and pathological innervation remain limited. Here, we found that senescent nucleus pulposus (NP) cells accumulated and released double-stranded DNA (dsDNA), which reinforced NP cell senescence and matrix catabolism. The accumulated dsDNA also activated cGAS-STING signaling, increased Netrin-1 expression, and promoted neuronal migration and neurite outgrowth. Guided by these findings, we developed RU@PEI-ZIF, a dual-functional nanoplatform combining PEI-mediated dsDNA scavenging with ZIF-8-mediated delivery of the cGAS inhibitor RU.521. RU@PEI-ZIF displayed dsDNA-binding capacity, cytocompatibility, and pH-responsive RU.521 release. In senescent NP cells, RU@PEI-ZIF reduced extracellular and cytosolic dsDNA, attenuated cGAS-STING-associated inflammatory and neurotrophic signaling, and reduced NP cell-mediated neuronal migration and neurite outgrowth. In an animal model of disc degeneration, intradiscal RU@PEI-ZIF reduced disc degeneration, NP cell senescence, pathological sensory innervation, and pain hypersensitivity. These findings support RU@PEI-ZIF as a dual-action nanotherapeutic strategy targeting both disc degeneration and pathological innervation.