ROS-responsive biomaterial delivery of the TCM-derived small molecule coptisine protects stem cells and attenuates intervertebral disc degeneration.

Oxidative stress compromise nucleus pulposus-derived mesenchymal stem cells (NPMSCs) and restrict endogenous repair in intervertebral disc degeneration (IDD). Here, human nucleus pulposus (NP) tissues showed that secreted phosphoprotein 1 (SPP1) expression increased with degeneration severity. Screening of 2,987 traditional Chinese medicine (TCM)-derived compounds, followed by cellular validation, identified coptisine as a candidate that reduced SPP1 expression while increasing NP-associated extracellular matrix components in NPMSCs. However, effective intradiscal delivery requires sustained local exposure within the adverse degenerative microenvironment. We therefore embedded coptisine-loaded poly (lactic-co-glycolic acid) microspheres in phenylboronic acid-modified gelatin methacryloyl to form an ROS-responsive depot (Cop@PLGA-GelMA-PBA). The composite showed sustained, oxidant-accelerated release and good cytocompatibility. Under H2O2 challenge, it preserved mitochondrial membrane potential and SOD2 abundance, while maintaining NP-associated extracellular matrix expression. Notably, SPP1 overexpression weakened these effects. When administered immediately after disc puncture, Cop@PLGA-GelMA-PBA maintained disc height and MRI signal, preserved tissue architecture and attenuated early degeneration. Collectively, these findings support responsive biomaterial delivery of a TCM-derived small molecule as a potential strategy for IDD.