A multifaceted strategy for intra- and extracellular nucleic acid regulation to alleviate intervertebral disc degeneration.

Abnormal accumulation of both intracellular and extracellular free nucleic acids drives chronic inflammation in intervertebral disc degeneration (IVDD). Despite the development of numerous minimally invasive treatments for IVDD, systematic approaches targeting the chronic inflammation mediated by both nucleic acid types are lacking. We propose a dual clearance strategy that inhibits mitochondrial DNA release inside nucleus pulposus cells while removing extracellular DNA from the disc microenvironment. Using single-cell sequencing and clinical samples, we revealed how both nucleic acid types drive inflammation. We then developed a targeted nanovesicle system delivering a mitochondrial membrane-stabilizing small molecule to block DNA leakage and inflammatory signaling, along with a hydrogel that captures extracellular DNA to prevent immune activation. In a rat model, this approach significantly slowed disease progression. This targeted dual nucleic acid clearance strategy provides a approach for treating IVDD and offers a theoretical framework for addressing other nucleic acid-related inflammatory diseases.