Brachyury‐Activated Fucoidan Hydrogel Microspheres Rejuvenate Degenerative Intervertebral Discs Microenvironment

Abstract Extracellular matrix (ECM) metabolic disorders and the establishment of inflammatory microenvironment are the primary pathological alterations associated with intervertebral disc degeneration (IVDD). The inflammatory microenvironment promotes ECM degradation, further exacerbating the vicious cycle of nucleus pulposus (NP) degeneration. This study introduces the mRNA encoding a novel therapeutic transcription factor, Brachyury (Bry), into nucleus pulposus cells (NPCs) using an injectable microsphere system composed of biomimetic GelMA/Fucoidan (FU) dual‐component hydrogel (GF) and surface chemically grafted lipid nanoparticles (LNP) (BLNP@GF). The study aims to alleviate inflammatory response in the NP while restoring the ECM secretion function of NPCs and enhancing the ability of NPCs to withstand inflammatory stress, thereby restoring physiological balance in the NP microenvironment. The GF microspheres demonstrate injectability and porosity, facilitating efficient LNP loading through chemical grafting. In the LPS‐simulated inflammatory microenvironment, sustained release of FU significantly reduces inflammatory activity in NPCs. Successful transfection with Bry mRNA upregulate ECM synthesis in degenerated NPCs. In a rat tail puncture IVDD model, local application of BLNP@GF microspheres effectively improved ECM remodeling in NP tissue, thereby ameliorating puncture‐induced IVDD. In conclusion, FU‐functionalized GelMA hydrogel microspheres loaded with Bry mRNA provide a promising new strategy for reversing IVDD.