A Single-Cell-Inspired Self-Enrichment Therapeutic Strategy Delays Intervertebral Disc Degeneration by Inhibiting Pyroptosis.

Abstract

Intervertebral disc degeneration (IVDD) is the primary reason for spinal surgery. Current therapies fail to halt or reverse its progression, largely because of the limited understanding and lack of targeted therapies for key mechanisms. This study aimed to integrate single-cell transcriptomics with clinical validation to construct a comprehensive cellular atlas for IVDD. The study uncovered a pronounced fibrotic barrier in degenerative tissues that severely impeded drug delivery and identified pyroptosis in nucleus pulposus cells driven by stimulator of interferon genes (STING)-mediated activation of multiple inflammatory pathways. To overcome these challenges, this study developed a self-enriching nanocarrier (Motor@TA-small interfering ribonucleic acid [siRNA]) that catalyzes hydrogen peroxide to generate asymmetric bubble propulsion, thereby enabling selective penetration into degenerated tissues without accumulation in healthy tissues. Tannic acid forms a hydrogen-bonded network with the siRNA, thereby enhancing its stability and delivery efficiency. The siRNA precisely targets the STING pathway to block inflammation-pyroptosis signaling at its source. Both the in vitro and in vivo results demonstrated that the nanocarrier possessed excellent biocompatibility and significantly delayed the progression of IVDD. This study presents a synergistic mechanism-target-material strategy that integrates pathological insight with advanced nanocarrier design, offering a promising platform for personalized IVDD therapy.