Inhibiting Immune Crosstalk by Modulation of the Intracellular Function and Extracellular Environment of Diseased Microglia to Boost Parkinson’s Disease Therapy

Microglia usually phagocytose excessive α-synuclein (α-syn) aggregates and turn into diseased analogues in Parkinson’s disease (PD), which can present α-syn-associated antigens, secrete cytokines and chemokines to recruit peripheral immune cells, and form strong immune crosstalk to aggravate PD progression. Hence, targeting the diseased microglia and inhibiting their immune crosstalk emerge as promising strategies for PD therapy. Herein, we reprogram the diseased microglia to efficiently degrade α-syn aggregates and neutralize neuroinflammatory factors to reduce the detrimental immune crosstalk and enhance therapeutic efficacy using rationally designed core–shell IHM nanoparticles, which consist of a ligustilide-functionalized Cu2-xSe nanoparticle (CSL NP) core and a hybrid cell membrane shell. The CSL NPs can redress the diseased microglia to reduce over-presented antigens by dual roles of reducing microglial RAGE-mediated phagocytosis of α-syn aggregates and increasing the microglial mature cathepsin D (m-CTSD) to efficiently degrade α-syn aggregates. The hybrid cell membrane shell is formed by a MES23.5 cell membrane (MCM) and IFN-γ-treated RAW264.7 cell membrane (IRCM). It can not only target diseased microglia by the specific interactions between VCAM-1 on the MCM and α4β1 integrin on the microglial membrane but also absorb and reduce the secretion of neuroinflammatory factors by diseased microglia through upregulated neuroinflammatory cytokine receptors such as IL1R1, TNFR1, and CCR2 on the surface of IRCM. The biomimetic core–shell IHM nanoparticles can be effectively delivered into the brain via meningeal lymphatic vessels to modulate the diseased microglia for boosting PD therapy. Our study demonstrates the promise of targeting diseased microglia to reduce their immune crosstalk in the treatment of PD and other neurodegenerative diseases.