Targeted delivery of IDR-1018 via biomimetic magnetic nanovesicles suppresses neurovascular cell death and promotes angiogenic repair after neonatal hypoxic-ischemic brain injury.

Neonatal hypoxic-ischemic brain damage (HIBD) is characterized by severe endothelial injury, inflammation, and apoptosis, which together contribute to irreversible neurodevelopmental deficits. In this study, we developed a biomimetic magnetic nanovesicle platform (IDR-MNC@RMVs) loaded with the host defense peptide IDR-1018 as a targeted therapeutic strategy for neonatal HIBD. Under external magnetic guidance, IDR-MNC@RMVs preferentially accumulated in ischemic brain regions, where they markedly reduced neuronal and vascular injury, attenuated brain atrophy, and improved neurological recovery in neonatal mice. Mechanistically, integrated analyses using single-cell RNA sequencing, transcriptomics, and functional assays showed that IDR-MNC@RMVs enhanced endothelial survival and angiogenic activity through activation of the ITGB3/VEGFA signaling axis. In vitro, IDR-MNC@RMVs protected hypoxia-injured human brain microvascular endothelial cells by restoring proliferation and migration while reducing apoptosis, whereas these protective effects were largely abolished after ITGB3 knockdown. In vivo, histological analyses further indicated reduced inflammatory injury and improved vascular preservation after treatment. Collectively, these findings identify IDR-MNC@RMVs as a promising nanotherapeutic strategy that promotes vascular repair and tissue recovery after neonatal hypoxic-ischemic injury. This work highlights the potential of combining biomimetic nanotechnology with peptide-based therapy for neonatal brain injury.