Triple Cross‐linked Dynamic Responsive Hydrogel Loaded with Selenium Nanoparticles for Modulating the Inflammatory Microenvironment via PI3K/Akt/NF‐κB and MAPK Signaling Pathways

Abstract Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri‐cross‐linked inflammatory microenvironment‐responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment‐responsive hydrogel (OD‐PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano‐fillers into the hydrogel results in extra cross‐linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple‐network is achieved. The hydrogel has injectable, self‐healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli‐responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH‐regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF‐κB and MAPK pathways, exerting anti‐inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple‐network structure provides an effective strategy to treat IDs, holding great promise in clinical application.