3‐D Sustained‐Release Culture Carrier Alleviates Rat Intervertebral Disc Degeneration by Targeting STING in Transplanted Skeletal Stem Cells

The hypoxic and high-pressure microenvironment of the intervertebral discs poses a major challenge to the survival and therapeutic efficiency of exogenous stem cells. Therefore, improving the utilization efficiency and therapeutic effect of exogenous stem cells to delay intervertebral disc degeneration (IVDD) is of great importance. Here, hypoxic induction studies are conducted in vivo and in vitro using rat costal cartilage-derived skeletal stem cells (SSCs) and find that hypoxia activates the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and increased reactive oxygen species (ROS) accumulation, triggering ferroptosis in SSCs through hypoxia-inducible factor-1 alpha-dependent mitophagy. Progressive hypoxia preconditioning reduce STING expression and ROS accumulation, inducing SSCs differentiation into nucleus pulposus-like cells via the Wnt signaling pathway. Considering this, a 3-D sustained-release culture carrier is generated by mixing SSCs with methacrylated hyaluronic acid and polydopamine nanoparticles coated with the STING inhibitor C-176 and evaluated its inhibitory effect on IVDD. This carrier is demonstrated to inhibit the cGAS/STING pathway and prevent ROS accumulation by continuously releasing C-176-coated polydopamine nanoparticles, thereby reducing ferroptosis, promoting differentiation, and ultimately attenuating IVDD, suggesting its potential as a novel treatment strategy.