Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold

Abstract Degeneration of fibrocartilaginous tissues is often associated with complex pro‐inflammatory factors. These include reactive oxygen species (ROS), cell‐free nucleic acids (cf‐NAs), and epigenetic changes in immune cells. To effectively control this complex inflammatory signaling, it developed an all‐in‐one nanoscaffold‐based 3D porous hybrid protein (3D‐PHP) self‐therapeutic strategy for treating intervertebral disc (IVD) degeneration. The 3D‐PHP nanoscaffold is synthesized by introducing a novel nanomaterial‐templated protein assembly (NTPA) strategy. 3D‐PHP nanoscaffolds that avoid covalent modification of proteins demonstrate inflammatory stimuli‐responsive drug release, disc‐mimetic stiffness, and excellent biodegradability. Enzyme‐like 2D nanosheets incorporated into nanoscaffolds further enabled robust scavenging of ROS and cf‐NAs, reducing inflammation and enhancing the survival of disc cells under inflammatory stress in vitro. Implantation of 3D‐PHP nanoscaffolds loaded with bromodomain extraterminal inhibitor (BETi) into a rat nucleotomy disc injury model effectively suppressed inflammation in vivo, thus promoting restoration of the extracellular matrix (ECM). The resulting regeneration of disc tissue facilitated long‐term pain reduction. Therefore, self‐therapeutic and epigenetic modulator‐encapsulated hybrid protein nanoscaffold shows great promise as a novel approach to restore dysregulated inflammatory signaling and treat degenerative fibrocartilaginous diseases, including disc injuries, providing hope and relief to patients worldwide.