Magnetic Hydrogels Deliver H 2 Se Spatiotemporally to Remodel the Regenerative Microenvironment and Accelerate Peripheral Nerve Repair

Abstract

Peripheral nerve repair is hindered by inflammation, oxidative stress, and poor vascularization. Current alternatives to autografts, such as drug‐loaded conduits, have limited blood‐nerve barrier penetration and function. Here, a repair system based on magnetothermal controlled release of hydrogen selenide (H 2 Se) is developed. The system integrates a topologically structured conduit (P(MMD‐CL)) and a thermoresponsive hydrogel (mPAAN) containing nanoparticles (mMNPs) loaded with the H 2 Se donor TDN1042. Under an alternating magnetic field (AMF), H 2 Se is controllably released and scavenges reactive oxygen species (ROS), and is transcriptionally associated with anti‐inflammatory macrophage polarization (NF‐κB/PPAR‐related pathways), as well as angiogenesis signaling (PI3K/AKT/eNOS and cGMP/PKG pathways). Transcriptomics revealed activation of scavenger receptor and ion channel activity, improved mitochondrial complex IV function, and enhanced energy metabolism and neural excitability. The layered hydrogel and aligned conduit further guide cell migration and nutrient transport. In rats, H 2 Se treatment achieved nerve regeneration and functional recovery comparable to autologous grafts. This synergistic gas, topological, and remote stimulation strategy offers a promising approach for neural repair.