Abstract
Parkinson's disease (PD) is characterized by dopamine (DA) neuron loss and neuroinflammation. This study develops carrier-free nanocapsules (NCs) for targeted delivery of DA and catalase (CAT) to the PD brain, addressing both DA depletion and neuroinflammation simultaneously. The NCs are engineered by DA and 4-formylphenylboronic acid co-loading with cRGD-modified CAT (CAT-cRGD) and surface-modifying with Angiopep-2 (Ang). Ang targets the blood-brain barrier (BBB), enhancing brain delivery, while cRGD targets upregulated integrin receptors in the PD-affected BBB. The NCs showed a 1.4-fold increase in parkinsonian brain targeting efficiency compared to normal mice. In PD mice models, NCs demonstrated a stable increase in learning and memory, enhanced locomotor activity, and improved motor coordination. DA supplementation significantly enhanced dopaminergic signaling, increasing DA levels 1.8- and 3.5-fold in the striatum and substantia nigra, respectively. Additionally, delivered CAT effectively reduced neuroinflammation by mitigating endoplasmic reticulum stress, slowing disease progression, and protecting DA from oxidation. This innovative approach using PD-targeted NCs represents a synergistic strategy for PD treatment, combining symptomatic relief with disease progression intervention.