Extracellular Vesicles as Nanotherapeutics for Parkinson's Disease

Abstract

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor-ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson's disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood-brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

Keywords: Parkinson’s disease; biomarkers; cell-free therapy; exosomes; extracellular vesicles; nanodrugs; nanoparticle; nanotherapeutics; neurodegeneration.

Figure 1

Schematic representation of biogenesis and release mechanisms for different types of extracellular vesicles.

Figure 2

Naturally occurring and engineered EVs as cell-free treatment for PD. EVs may be manipulated to deliver: (i) anti-oxidant agents (e.g., curcumin, catalase or ApoD) which protect neurons from oxidative stress; (ii) growth factors (e.g., GDNF) to stimulate proliferation of DAergic neurons; (iii) DA to ameliorate behavioral parameters; (iv) siRNAs silencing the expression of SNCA gene to decrease α-Syn levels. Different routes of administration (systemic injection, intranasal injection and intraperitoneal injection) may be used to treat PD mouse models.

Figure 3

Naturally occurring and engineered EVs in the treatment of PD: mechanism of action. Following their administration, EVs cross the BBB to reach the brain, where they target neurons and glial cells. Among the effects in EV recipient cells: (i) production of anti-oxidant molecules, (ii) reduction of neuroinflammation, (iii) decrease in α-Syn levels, (iv) increase in DA bioavailability.