Robust neuroprotective effects of intranasally delivered iNOS siRNA encapsulated in gelatin nanoparticles in the postischemic brain

The therapeutic efficacy of intranasal iNOS siRNA delivery was investigated in the postischemic rat brain after encapsulating on in gelatin nanoparticles (GNPs; diameter 188.0 ± 60.9 nm) cross-linked with 0.0667% glutaraldehyde (GA). Intranasally delivered GNPs were found in extracellular and intracellular compartments of many brain regions, including the olfactory bulb, cerebral cortex, and striatum at 1 hour after infusion and continued to be detected for days. Infarct volumes were markedly suppressed (maximal reduction to 42.1 ± 2.6%) at 2 days after 60 minutes of middle cerebral artery occlusion (MCAO) when iNOS siRNA/GNPs were delivered at 6 hours post-MCAO. In addition, this protective effect was manifested by reductions in neurological and behavioral deficits that were sustained for 2 weeks. Therapeutic potency of iNOS siRNA/GNPs was significantly greater and sustained longer than that of bare siRNA and prolonged and efficient iNOS by iNOS siRNA/GNP is responsible for the robust neuroprotective effect.

Intranasal administration of iNOS siRNA/GNP markedly suppressed infarct volumes, which was accompanied by long-term improvements in neurological deficits and motor impairments. iNOS siRNA bound to the gelatin matrix is released intracellularly or extracellularly as the gelatin is degraded enzymatically, resulting in iNOS suppression and subsequent neuroprotective effect. Importantly, the therapeutic potency of iNOS siRNA/GNPs was significantly greater than that of bare siRNA. This is the first systematic analysis of the therapeutic efficacy of combining siRNA-mediated gene knock-down-based therapy, GNP-encapsulation, and intranasal delivery in an animal disease model, demonstrating a huge therapeutic potential of this approach for diverse brain diseases.Figure optionsDownload high-quality image (202 K)Download as PowerPoint slide