Post-transcriptional knockdown of BRCC3 via siRNA-loaded niosomes modulates autophagy and endoplasmic reticulum stress in rotenone-induced Parkinson's Disease model

Parkinson's Disease (PD) is a prevalent neurodegenerative disorder. Recent studies implicate BRCA1-/BRCA2-containing complex 3 (BRCC3) in PD-related mechanisms such as ubiquitin-proteasome system dysfunction. This study aimed to evaluate the therapeutic potential of BRCC3 silencing via systemically administered siRNA-loaded niosomes in a rotenone-induced rat model of PD. Niosomes were synthesised by thin-film hydration, and three BRCC3-targeted siRNA sequences were tested in primary midbrain dopaminergic neurons. The most effective sequence, identified by Real-Time Quantitative PCR (RT-qPCR) and immunofluorescence, was used for in vivo studies. The PD model was induced in adult male rats (n = 24/group) by subcutaneous rotenone administration (2 mg/kg/day) for 35 days. In the in vivo phase of the study, behavioural, biochemical, in vivo imaging (IVIS), histological, and RT-qPCR analyses were performed. IVIS analysis confirmed brain accumulation of niosome-siRNA complexes within 3-5 h. Complementary analyses demonstrated that siRNA treatment significantly enhanced locomotor performance, restored redox homeostasis and dopamine levels, attenuated neuronal loss, upregulated autophagy-related proteins (↑LC3-II, ↑Beclin), suppressed endoplasmic reticulum stress markers (↓GRP78/Bip, ↓CHOP), elevated tyrosine hydroxylase expression, and reduced α-synuclein accumulation. In conclusion, siRNA-mediated suppression of BRCC3 via siRNA-loaded niosomes provides neuroprotection by modulating autophagy, ER stress, and antioxidant pathways, supporting BRCC3 as a promising therapeutic target for PD.