Microenvironment Remodeling Microgel Repairs Degenerated Intervertebral Disc via Programmed Delivery of MicroRNA-155

The progression of intervertebral disc degeneration (IVDD) is associated with increased cell apoptosis and reduced extracellular matrix (ECM) production, both of which are driven by ongoing inflammation. Thus, alleviating the acidic inflammatory microenvironment and mitigating the apoptosis of nucleus pulposus cells (NPCs) are essential for intervertebral disc (IVD) regeneration. Regulating pH levels in the local environment can reduce inflammation and promote tissue recovery. In this study, a lactic acid-capturing microgel carrying a functionalized miRNA-155 nanocarrier was designed for IVD regeneration. microRNA-155 was loaded into the NPC-targeted nanogel via host-guest binding. The miR-155 nanocarrier (NGM) achieved lactic acid-sensitive release of miRNA-155, resulting in rapid regulation of apoptosis. Moreover, SS31, which dissociated from the nanogel network, had the ability to regulate mitochondrial metabolism. Moreover, the microgel was constructed using a matrix metalloproteinase-responsive peptide. The chitosan coating on the microgel system was ingeniously employed to capture lactic acid and enable pH-responsive dissociation, thereby alleviating the acidic microenvironment to protect cell viability and facilitate the delivery of the NGM. The microgel system effectively promoted IVD regeneration by alleviating the acidic microenvironment and preventing NPC apoptosis.