Carrier-free quercetin nanomedicine blocks NLRP3 deubiquitination and TXNIP recruitment for Parkinson’s disease therapy

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a key drug target for Parkinson's disease (PD) therapeutics. Identifying the underlying upstream mechanisms of assembly formation is crucial for clarifying the exact pharmacological effects, but currently remains elusive for most drugs. Here, we develop a carrier-free nanomedicine (NanoQC) derived from natural phytochemical quercetin (QC) to mitigate neuroinflammation and neurodegeneration for PD treatment and demonstrate that it attenuates aberrant inflammasome assembly and activation through inhibiting the deubiquitination of NLRP3 and blocking its interaction with thioredoxin-interacting protein (TXNIP). Intranasal NanoQC administration alleviates nigral dopaminergic neuronal loss and striatal dopamine depletion, while improving nigral dopaminergic neuronal excitability and hippocampal synaptic plasticity, relieving olfactory dysfunction, ultimately ameliorating motor and memory impairments in PD mice. This work demonstrates the great promise of NanoQC inhibiting the upstream mechanisms of NLRP3 inflammasome assembly to combat PD, providing novel insight for precise target identification of nanomedicines.