Versatile Microgel Platform for Intervertebral Disc Degeneration Therapy: Targeting Pericyte-Mediated Fibrosis and Protecting Nucleus Pulposus Cells.

Fibrosis is both a consequence and a driving factor of intervertebral disc degeneration (IVDD); however, the origins, pathways, and regulatory mechanisms of fibrotic effector cells remain incompletely understood, complicating antifibrotic therapy development. In this study, we identified pericytes as novel fibrotic effector cells in IVDD, contributing to fibrosis through activation of the TGF-β signaling pathway. To address this, we developed a microgel platform (MMS@TRP) designed to specifically inhibit pericyte activation and pro-fibrotic transition. MMS@TRP was constructed by integrating a tetrahedral framework nucleic acid (tFNA)-based nanocarrier (TRP), which encapsulates a miR-21 inhibitor and is conjugated with a pericyte-targeting peptide (pPB), onto tannic acid (TA)-based metal-phenolic network (MPN)-functionalized gelatin methacryloyl microspheres (GelMA MS). This microgel system protects TRP from enzymatic degradation by nucleases while facilitating its pH-sensitive release. The early-stage release of TRP from MMS@TRP ensures targeted delivery of the miR-21 inhibitor to pericytes, suppressing pericyte proliferation, migration, and myofibroblast transition by blocking the TGF-β signaling pathway. Simultaneously, sustained TA release provides prolonged protection to nucleus pulposus cells (NPCs) through reactive oxygen species (ROS) scavenging, mitochondrial preservation, and anti-inflammatory effects. Collectively, the MMS@TRP platform presents a versatile and innovative approach for mitigating IVDD by inhibiting fibrosis and protecting NPCs.