Chitosan-based nanoparticles for targeted delivery of 17β-estradiol to enhance SIRT1-mediated autophagy and mitigate rotenone-induced Parkinson's disease

The pathogenesis of Parkinson's disease (PD) is closely linked to the dysregulation of the clearance mechanism responsible for degrading misfolded proteins and malfunctioning organelles. Thus, maintaining a balance in autophagy is essential for managing PD. 17β-Estradiol (E2) is a specific calpain inhibitor, where the latter is upregulated in the PD brain and is responsible for inducing apoptosis. However, its peripheral toxicity and hydrophobicity hinder the investigation of its therapeutic potential. To address this, a neuroprotective and biocompatible chitosan nanoparticle, conjugated with DRD3 (Ab-ECSnps), is engineered to enable active targeting. The nanoformulation with immense potential for inhibiting calpain downregulates caspase 3-mediated apoptosis in the rotenone-treated PD model. Neuroprotection conferred by the nanoformulation is not solely due to apoptosis inhibition. Interestingly, the study reveals that the simultaneous induction of SIRT1- and LAMP2-mediated autophagy enhances autophagic flux, as supported by the upregulation of beclin, VPS34, and an increase in the number of lysosomes. The nanoformulation also clears pathological pSer129-synuclein and protects substantia nigra dopaminergic neurons in rotenone-induced Parkinson's disease models. This non-invasive, dopaminergic neuron-targeted delivery system, with its excellent biocompatibility, maintains a balance between apoptosis and autophagy, making it a promising approach for treating and preventing Parkinson's disease.