Liposomes-loaded miR-128-3p exert neuroprotective effects in hypoxia-ischemia injury by targeting Rgs1 in neonatal mice

Perinatal brain injury due to severe hypoxia-ischemia (HI) is a significant cause of neonatal mortality and high prevalence of long-term chronic disease on a global scale, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. MiRNA-128 is a brain-enriched microcoding RNA that is highly expressed in the central nervous system. In this study, we found that miR-128-3p expression, a predicted down-regulated microRNA (miRNA) in GSE213067, was significantly reduced in ipsilateral cortical tissues after HI injury in pups. Then we successfully constructed a well-dispersed and uniformly sized liposome-encapsulated miR-128-3p nanoparticle (miR-128-3p@Lipo), with exhibited good stability and biosafety. Moreover, the use of a miR-128-3p@Lipo nanoparticle delivery system could simultaneously deliver miR-128-3p to neuron via a non-invasive intranasal route. Up-regulation of miR-128-3p levels in the ipsilateral cortical tissues via miR-128-3p@Lipo significantly ameliorated cerebral infarcts, apoptosis, neuroinflammation, and reactive oxygen species levels and facilitated the recovery of neurological function after HI injury in neonatal mice. Further mechanistic exploration revealed that miR-128-3p may exert neuroprotective effects by inhibiting the expression of the downstream target gene Regulating G protein signaling 1 (Rgs1). This work suggests that miRNAs offer a therapeutic potential to mitigate HI brain damage in neonatal mice.