Dynamic adaptive coassembled sericin protein orchestrating stem cell development for nucleus pulposus regeneration.

The zonal structure of natural extracellular matrix (ECM) creates a dynamic microenvironment that regulates mechanical and biochemical signals to support stem cell development. Here, we engineered a dynamic adaptive protein gel by coassembling bioactive sericin with an amphiphilic tripeptide, forming a nucleus pulposus (NP)-like viscoelastic network with rapid stress relaxation. This coassembled protein gel sequentially activated integrin β3-mediated mechanotransduction, promoted cytoskeletal remodeling and Yes-associated protein nuclear translocation, and subsequently up-regulated bioactive factors and ECM synthesis to orchestrate stem cell development. Incorporation of kartogenin provided sustained chondrogenic cues, thereby promoting stem cell differentiation and preserving NP tissue integrity in vivo. Together, these findings establish a phase separation-driven, adaptive protein matrix that orchestrates both mechanical and biochemical signaling for robust intervertebral disc regeneration.