Modulating SQSTM1/p62-dependent selective autophagy of neurons by activating Nrf2 with multifunctional nanoparticles to eliminate α-synuclein aggregates and boost therapy of Parkinson’s disease

The misfolding and aggregation of α-synuclein is one of the key pathogeneses in Parkinson's disease (PD). Development of innovative and effective approaches to eliminate α-synuclein aggregates is crucial for PD treatment. Herein, we report that quercetin-modified ultrasmall Cu2-xSe antioxidative nanoparticles (abbreviated as CSPQ) can promote neurons to efficiently scavenge α-synuclein aggregates and boost PD therapy by activating their nuclear factor-erythroid 2-related factor 2 (Nrf2) to enhance the SQSTM1/p62-dependent selective autophagy. We reveal that CSPQ nanoparticles can promote the degradation of Kelch-like ECH-associated protein 1 (Keap1) and thus activate Nrf2/p62 pathway of neurons by stimulating their nuclear translocation of transcription factor EB (TFEB). Moreover, these nanoparticles can successfully reduce α-synuclein associated pathology to alleviate neuronal damage in vivo and improve motor disorder and exploration ability of α-synuclein preformed fibrils (PFFs)-induced PD mice. Our work demonstrates the importance and novelty of modulating the selective autophagy of neurons by nanoparticles in clearance of α-synuclein aggregates for PD therapy, and highlights the great potential of CSPQ nanoparticles in PD therapy.