Rabies virus glycoprotein (RVG29)-linked microRNA-124-loaded polymeric nanoparticles inhibit neuroinflammation in a Parkinson's disease model

In the present study, we have prepared microRNA(miR)-124-loaded Rabies virus glycoprotein (RVG)29 surface-conjugated polymeric nanoparticles (NPs) to improve neuroinflammation in Parkinson's disease (PD). We hypothesize that an increase in the intracellular concentration of miR-124 will result in a better prognosis for Parkinson's disease. Minimal toxicity for the RVG29 NPs was observed at concentrations < 100 mu g/mL, while the cell viability of cells treated with blank NPs at concentrations of 200 mu g/mL markedly decreased, indicating the safety of the carrier system. Results showed that mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6, significantly increased upon lipopolysaccharide (LPS) administration. However, the mRNA levels of these cytokines reflected those of the miR-NPs-treated control group, indicating the influence of miR-124 exposure. After transfection with miR-NPs, levels of pro-inflammatory cytokines and neuroprotective molecules were reduced and increased, respectively. Administration of LPS significantly increased the levels of mitogen activated protein kinase kinase kinase (MEKK)3 and P-P65 levels, while transfection with miR-NPs significantly reduced the expression of both MEKK3 and P-P65, reflecting that of the control. This research has revealed that miR-124 could target both the MEKK3 and nuclear factor kappa light chain enhancer of activated B cell (NF-Kb) pathways, while also reducing inflammatory cytokine levels. In addition, a 3-fold decrease in apoptosis was observed in miR-NP transfected cells. The exogenous delivery of miR-NPs significantly downregulated MEKK3 expression in animal studies, as outlined by immunohistochemical staining (IHC). Overall, miR-NPs have the potential to inhibit pro-inflammatory signaling and enhance neuroprotection in PD.