| Summary: | Abstract Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a “Trojan horse” system is used for substantia nigra‐targeted delivery of a blood brain barrier‐penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4′‐dimethoxychalcone (DMC) (designated as RVG‐nDMC). Here, the neuroprotective effects of DMC are demonstrated in PD. Specifically, RVG‐nDMC penetrates the blood brain barrier with enhanced brain‐targeted delivery efficiency and is internalized by DA neurons and microglia. In vivo studies demonstrate that RVG‐nDMC ameliorates motor deficits and nigral DA neuron death in PD mice without causing overt adverse effects in the brain or other major organs. Moreover, RVG‐nDMC reverses tyrosine hydroxylase ubiquitination and degradation, alleviates oxidative stress in DA neurons, and exerts antiinflammatory effects in microglia. The “Trojan horse” strategy for targeted delivery of DMC thus provides a potentially powerful and clinically feasible approach for PD intervention.
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