Biomimetic nanodelivery system with simultaneous blood–brain barrier-crossing and neuroprotective abilities for anti-parkinsonian therapy

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BACKGROUND: Parkinson's disease (PD) has emerged as a critical public health challenge amidst global population aging. The pathogenesis of PD is extremely complex. Notably, evidence showed that neuroinflammation due to microglial activation is a critical driver of dopaminergic neuron loss in patients with PD. Therefore, several strategies aimed at alleviating neuroinflammation are currently being tested for the treatment of PD. However, current anti-inflammatory agents exhibit limited therapeutic efficacy in vivo due to hindrances caused by the blood-brain barrier (BBB). To overcome BBB-related challenges, we developed a biomimetic nanodelivery system (DCM@Nar-NCs) by encapsulating naringenin nanocrystals (Nar-NCs) within differentiated HL-60 cell membranes. Our analysis demonstrated that DCM@Nar-NCs could act as an innovative nanoplatform for PD therapy, showing BBB penetration capabilities and exhibiting precise accumulation at sites of neuroinflammation. This targeted delivery enables more precise and potent treatment than existing therapeutic modalities. METHODS: The BBB penetration efficiency and brain-targeted delivery of DCM@Nar-NCs were assessed both in vitro and in vivo. The neuroprotective effects were comprehensively investigated in cellular and animal levels. Finally, the ability of DCM@Nar-NCs to ameliorate motor dysfunction and cognitive impairment was validated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. RESULTS: DCM@Nar-NCs exhibited significantly enhanced BBB permeability and could exert dual therapeutic effects. Notably, DCM@Nar-NCs modulated microglial polarization (pro-inflammatory M1 phenotype to neuroprotective M2 phenotype), thereby attenuating neuroinflammatory cascades. Additionally, DCM@Nar-NCs could ameliorate mitochondrial dysfunction and thereby prevent the apoptosis and destruction of dopaminergic neurons. Finally, behavioral assessments in animal models confirmed the remarkable capacity of DCM@Nar-NCs to reverse PD-related motor deficits and cognitive impairment. CONCLUSION: Collectively, the novel PD treatment approach developed in this study offers superior biosafety and treatment efficacy, highlighting its strong potential for clinical translation.

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