Self-cascade ROS-trapping bioreaction system reverses stem cell oxidative stress fate for osteogenesis

Reactive oxygen species (ROS) scavenging is essential for periodontal regeneration. However, the dynamic change of the applied materials within the ROS-rich environment and the residual oxidation products in the host highly impact periodontal regeneration. This study successfully constructs a bioreaction system via thiol-ene click chemistry, leveraging the high affinity of glutathione (GSH) for ROS to attract excess ROS to the crosslinking points. Two minutes after hydrogen peroxide (H₂O₂) treatment, the ROS level in the G8–0 hydrogel acutely decreases, reaching a 4.4 % reduction within 10 minutes, confirming the ROS-trapping efficacy. Through a ‘bait switch-on’ mechanism, hexagonal boron nitride (hBN) takes over the captured ROS and the oxidation products of pectin further drive the reduction reaction, ultimately restoring the extracellular environment. The self-cascade products, oxidized hBN, reshape the intracellular oxidative stress (OS) environment, achieving a synergistic extra- and intra-cellular treatment. The significantly high reduced to oxidized glutathione (GSH/GSSG) ratio in G8–10 hydrogel (∼80 %) illustrates a reversal of oxidative stress in bone marrow stem cells (BMSCs). On a molecular level, the bioreaction system inhibits the NF-κB pathway, promoting the expression of key antioxidant genes (Nqo1 and Nrf2) and osteogenic molecules (ALP and OCN), thereby reversing the detrimental effects of OS on BMSCs. In vivo application demonstrated the system’s strong redox-balancing and osteogenic capabilities in the periodontal inflammation environment. This novel antioxidant bioreaction system, characterized by self-cascade ROS-trapping and product utilization, offers innovative treatment strategies for tissue regeneration under conditions of excessive OS.