Baicalein-loaded procyanidins nanoparticles alleviate neuroinflammation in Parkinson's disease by restoring microglial 8-oxoguanine DNA glycosylase 1.

Abstract

Microglial NLRP3 inflammasome activation and M1 polarization, driven by unresolved 8-oxoguanine (8-oxoG) DNA damage resulting from downregulated 8-oxoguanine DNA glycosylase 1 (OGG1), are key drivers of neuroinflammation in Parkinson's disease (PD). Baicalein (BAI) can restore OGG1 and interrupt this pathological cycle, but its poor solubility and low brain accumulation limit its therapeutic efficacy. Procyanidins (PC), a class of flavanol polyphenols with neuroprotective and anti-inflammatory effects, can self-assemble into nanoparticles (PC NPs) to encapsulate hydrophobic BAI while exerting synergistic therapeutic effects. However, PC NPs alone fail to overcome three sequential biological barriers for PD treatment: systemic clearance, blood brain barrier (BBB) transcytosis, and selective microglial uptake. To tackle these challenges, we engineered a cascade-delivery nanoplatform named RVG/MG1-M@PC@BAI NPs for the co-delivery of BAI and PC. In this system, PC forms self-assembled inner core to encapsulate BAI. This core is further coated with an immune-evasive hybrid membrane (M) surface-functionalized with RVG29 peptide for BBB penetration and MG1 peptide for selective M1 microglial uptake. In vitro and in vivo characterization demonstrated that the nanoplatform effectively penetrates the BBB and is preferentially internalized by microglia. Pharmacological evaluation demonstrated that the nanoplatform efficiently upregulates OGG1 expression, thereby reducing 8-oxoG accumulation, suppressing aberrant NLRP3 inflammasome activation, restoring the physiological balance of microglial M1/M2 phenotypes, and ultimately alleviating neuroinflammation. Safety assessment confirmed its favorable biocompatibility. In conclusion, RVG/MG1-M@PC@BAI NPs represent an OGG1-targeted synergistic nanoplatform, providing a promising strategy for PD therapy.