Sequential redox control and SDF-1α release by diselenide-bridged mesoporous silica nanoparticles promote...

Intervertebral disc degeneration (IVDD) is characterized by overactive oxidative stress, uncontrolled inflammation, and the deterioration of extracellular matrix (ECM). Deciphering the spatiotemporal cues of the complicated microenvironment would facilitate the development of new therapeutic strategies. In this study, we reveal that increased expression of oxidative stress markers is strongly associated with pro-inflammatory markers at the early stage, whereas the level of ECM repair markers is elevated at the late stage. Hypothesizing that sequentially targeting redox, inflammation, and ECM repair would be beneficial to IVDD management, we report the development of diselenide-bridged mesoporous silica nanoparticles (MSNs) loaded with SDF-1α. Redox-responsive MSNs not only efficiently neutralize ROS in damaged nucleus pulposus (NP) cells and macrophages to ameliorate oxidative stress and inflammation at the early stage via inhibiting the NF-κB pathway, but also sequentially release SDF-1α to facilitate ECM repair at the late stage via activating the PI3K-AKT-mTOR pathway. Leveraging such a time-sequenced microenvironment regulation mechanism, MSN@SDF-1α attenuates inflammation, maintains NP water content, and induces mesenchymal stem cells (MSCs) homing, leading to the structural regeneration of intervertebral discs in a puncture model. Our study proposes a mechanism-driven therapeutic approach that integrates insights into redox, inflammation, and ECM repair with the advanced design of versatile bioactive materials, offering a promising strategy for precise intervertebral disc regeneration.