Bioactive Silk Fibroin Hydrogel Harnesses BMSCs‐EVs to Modulate Inflammatory Microenvironment in Intervertebral Disc Degeneration

Intervertebral disc degeneration (IVDD) is a common age‐related disorder associated with inflammation, pain and impaired mobility. In this study, we developed a therapeutic system using silk fibroin (SF) hydrogel loaded with mRNA‐engineered extracellular vesicles derived from murine bone marrow mesenchymal stem cells (BMSCs‐EVs) to modulate macrophage polarization and alleviate IVDD. BMSCs were isolated from 6‐week‐old C57BL/6 mice, and an acute IVDD model was established via 18G needle puncture of the coccygeal discs (Co7‐Co10). RAW 264.7 murine macrophages were used for in vitro assays, with M1 polarization induced by LPS and IFN‐γ. The SF/EVs complex was characterized by SEM, FTIR and rheology, confirming its structural suitability for EV delivery. Functionally, SF hydrogel not only served as a biocompatible carrier but also enabled sustained release of EVs, enhancing their anti‐inflammatory effects. In vitro, SF/EVs inhibited M1 polarization and promoted M2 marker expression. In vivo implantation improved disc histology and reduced inflammatory macrophage infiltration. High‐throughput RNA sequencing identified S100B as a key functional cargo within EVs. Lentivirus‐mediated overexpression and knockdown experiments confirmed that EV‐derived S100B suppresses M1 polarization and mitigates IVDD progression. In summary, SF hydrogel loaded with S100B‐enriched BMSCs‐EVs offers a promising strategy to reshape the inflammatory microenvironment and promote disc regeneration in IVDD.