Engineered Extracellular\nVesicle-Based Nanoformulations\nThat Coordinate Neuroinflammation and Immune Homeostasis, Enhancing\nParkinson’s Disease Therapy

Although conventional intervention to microglia can mitigate\nneuroinflammation\nin the short term, immune disorders by peripheral inflammatory cells\ncan infiltrate continuously, resulting in an overactivated immune\nmicroenvironment of Parkinson’s disease (PD). Here, we design\nengineered extracellular vesicle-based nanoformulations (EVNs) to\naddress multiple factors for the management of PD. Specifically, EVN\nis developed by coating CCR2-enriched mesenchymal stem cell-derived\nextracellular vesicles (MSC<sup>CCR2</sup> EVs) onto a dihydrotanshinone\nI-loaded nanocarrier (MSeN-DT). The MSC<sup>CCR2</sup> EVs (the shell\nof EVN) can actively show homing to specific chemokines CCL2 in the\nsubstantia nigra, which enables them to block the infiltration of\nperipheral inflammatory cells. Interestingly, MSeN-DT (the core of\nEVN) can promote the Nrf2–GPX4 pathway for the suppression\nof the source of inflammation by inhibiting ferroptosis in microglia.\nIn the PD model mice, a satisfactory therapeutic effect is achieved,\nwith inhibition of peripheral inflammatory cell infiltration, precise\nregulation of inflammatory microglia in the substantia nigra, as well\nas promotion of behavioral improvement and repairing damaged neurons.\nIn this way, the combinatorial code of alleviation of inflammation\nand modulation of immune homeostasis can reshape the immune microenvironment\nin PD, which bridges internal anti-inflammatory and external immunity.\nThis finding reveals a comprehensive therapeutic paradigm for PD that\nbreaks the vicious cycle of immune overactivation.