Gene‐Engineered Nucleus Pulposus‐Mimetic Microspheres Reshaping the Hydration Microenvironment to Delay Intervertebral Disc Degeneration

ABSTRACT The hydration microenvironment relies on a proteoglycan matrix and aquaporins (AQPs) to maintain water homeostasis, crucial for tissue function. During disc degeneration, the loss of matrix integrity and AQP‐mediated water transport accelerates tissue failure. Existing hydrogel materials provide structural support but do not fully regulate hydrated homeostasis, making it difficult to halt degeneration. Here, we designed a GBA/SRGN@HADA@GelMA biomimetic nucleus pulposus system to remodel the hydrated niche. The system employs GelMA microspheres to establish a hydro‐retentive matrix with enhanced mechanical stability. A dopamine‐modified hyaluronic acid (HADA) coating leverages HA hydrophilicity to replenish water and improve lubrication, while dopamine contributes adhesion and antioxidant protection to relieve stress and support AQP‐mediated water flux. Furthermore, the chemically modified GBA/SRGN complex is anchored to the microsphere surface through amide bonding and electrostatic adsorption, enabling nucleic acid protection and controlled release. In vitro and in vivo, the system curbs inflammation and safeguards the extracellular matrix (ECM), bolstering the swelling pressure, hydration, and mechanical stability of the nucleus pulposus. Transcriptomics reveals Adcy upregulation and cAMP–PKA–CREB activation, promoting AQP1 transcription and membrane localization to enhance transmembrane water transport. A biomimetic microsphere system for hydration microenvironment remodeling offers a precise intervention in degenerative intervertebral discs.