Nanoparticle-mediated sodium butyrate delivery for repairing hypoxic-ischemic brain injury in premature infants

Hypoxic-ischemic encephalopathy of prematurity (HIEP) is a leading cause of acute mortality and chronic neurological injury in premature infants. This study investigates the molecular mechanisms by which magnetic fluorescent nanoparticles loaded with sodium butyrate (MNs@SB) repair HIEP by modulating the Sp1 and TGF-β1 signaling pathways. Untargeted metabolomics analysis revealed significant suppression of the butyrate metabolism pathway in the intestinal tissues of HIEP mice. We synthesized and characterized MNs@SB nanoparticles, with zeta potential and DLS results indicating an average nanoparticle size of approximately 79.89 nm and a zeta potential of -36.87 mV. TEM images confirmed that the nanoparticles formed polymer-coated clusters. MNs@SB demonstrated excellent biocompatibility and stable magnetic targeting behavior. The nanoparticles were delivered to the brain via tail vein injection and magnetic targeting, with focused ultrasound facilitating their diffusion. The results showed that HIEP mice exhibited a significant increase in infarct size and extensive tissue loss, whereas MNs@SB treatment effectively reversed HIEP-induced brain damage, improving both short-term and long-term neurological deficits. Single-cell RNA sequencing and high-throughput transcriptome analysis revealed that MNs@SB promoted brain repair by upregulating neuronal Sp1, activating the TGF-β1 signaling pathway, and inhibiting neuronal apoptosis. In vivo experiments further confirmed that MNs@SB treatment restored SP1 mRNA and protein expression in the brain. Additionally, MNs@SB treatment significantly restored TGF-β1, p-SMAD2, and p-SMAD3 protein expression, indicating activation of the TGF-β1/SMAD2/3 signaling pathway. This study presents a novel nanomedicine therapeutic strategy with potential clinical applications.