A programmed Ca2+ nanomodulator by dynamically regulating autophagy and neuroinflammation for Parkinson's disease therapy

Effective programming of calcium ion (Ca 2+ ) is critical and challenging for Parkinson's disease (PD) therapy due to the requirement of both the promotion of Ca 2+ influx to activate lysosomal autophagy pathway and the reduction of Ca 2+ level for inhibiting neuroinflammation. Herein, an engineering ginger-extracellular vesicles (CQGE) with a programmed Ca 2+ regulation is designed to dynamically balance the contradiction between autophagy and anti-inflammation according to the varied stage in PD therapy. Specifically, the ginger-derived extracellular vesicles (GEVs) with high content of 6-shogaol were fused with the targeted nanomicelles (CQ) containing quercetin to develop CQGE. The weak hydrophilic of 6-shogaol priority facilitated its rapid extracellular release to stimulate Ca 2+ influx, thereby activating lysosomal autophagy pathway (CaMKK2/AMPK/mTOR) for the degradation of α-synuclein aggregation. Subsequently, the strong hydrophobic of quercetin then released slowly in the neurons, leading to sustained reduction in Ca 2+ level by chelation to inhibit neuroinflammation and promote the repair of neurons. Such a programmable Ca 2+ nanomodulator exhibited a promising therapeutic strategy on the enhancement sequentially of the neuronal autophagy, degradation of α-synuclein and anti-inflammatory, implementing the behavioral improvements and neural functional recovery in PD model mice.