Mesenchymal Stem-Cell-Derived Exosomes Loaded with Phosphorus Dendrimers and Quercetin Treat Parkinson's Disease by Modulating Inflammatory Immune Microenvironment.

The intricate pathologic features of Parkinson's disease (PD) coupled with the obstacle posed by the blood-brain barrier (BBB) significantly limit the efficacy of most medications, leading to difficulties in PD treatments. Herein, we have developed a nanomedicine based on stem-cell-derived exosomes coloaded with hydroxyl-terminated phosphorus dendrimers (AK76) and quercetin (Que) for combined therapeutic intervention of PD. The engineered nanocomplexes (for short, QAE NPs) exhibit an optimal size of 269.7 nm, favorable drug release profile, and desired cytocompatibility, enabling penetration of the nasal mucosa to accumulate in the brain without BBB crossing. The developed QAE NPs can scavenge reactive oxygen species, promote M2 microglial polarization, attenuate inflammation, and protect neurons by inducing autophagy and restoring mitochondrial homeostasis through the integrated anti-inflammatory and antioxidant properties of exosomes, Que and AK76, collectively leading to improved motor functions, coordination, and alleviation of depression-like symptoms in PD mice. The formulated QAE NPs combined with several therapeutic components are able to simultaneously modulate both microglia and neurons, offering promising potential for the treatment of PD and other neurodegenerative disorders.