Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges

Abstract

Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated and used methods. Drugs can hijack RMT by expressing specific ligands that bind to receptors mediating transcytosis, such as the transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (INSR). Cell-penetrating peptides and viral components originating from neurotropic viruses can also be utilized for the efficient BBB crossing of therapeutics. Exosomes, or small extracellular vesicles, have gained attention as natural nanoparticles for treating CNS diseases, owing to their potential for natural BBB crossing and broad surface engineering capability. RMT-mediated transport of exosomes expressing ligands such as LDLR-targeting apolipoprotein B has shown promising results. Although surface-modified exosomes possessing brain targetability have shown enhanced CNS delivery in preclinical studies, the successful development of clinically approved exosome therapeutics for CNS diseases requires the establishment of quantitative and qualitative methods for monitoring exosomal delivery to the brain parenchyma in vivo as well as elucidation of the mechanisms underlying the BBB crossing of surface-modified exosomes.

Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges

“…However, it has been demonstrated that when exosomes are administered externally (i.e., intravenously), a large fraction of systemically injected exosomes quickly become trapped in hepatic or splenic tissues due to their specialized subsets of phagocytic immune cells and extensive capillary network [ 58 ]. Because of this, many techniques have been developed to target these vesicles to the brain and improve their penetration through the BBB [ 59 , 60 , 61 ] ( Figure 2 ). The conjugation of specific ligands to the surface of exosomes increases the interaction with the target cells, and the addition of labeled fluorescent dyes or radioactive MRI agents is an efficient method for in vivo tracking [ 62 ].…”

“…The application of a natural receptor on exosomes’ luminal surface is widely used to increase the exosome transcytosis rate through the BBB. In this sense, TfR, INSR, and especially LDLRs are of great interest [ 61 ]. LDLR is widely expressed in the brain and is able to attach to different ligands (in addition to lipoprotein metabolism) to mediate endothelial transcytosis and address the endocytic cargo to the lysosomes [ 59 ].…”

Liposomes: An emerging carrier for targeting Alzheimer's and Parkinson's diseases

“…For this, drug-loaded liposomes are surface-functionalized or conjugated with suitable ligands (macromolecules such as peptides, antibodies, and aptamers), which enhance, at least in part, the pharmacokinetics and bio-distribution of liposomes [ 73 ]. The surface-functionalized ligand recognizes and binds to the specific receptors expressed on the brain endothelial cells' surface and penetrates across the BBB [ 74 , 75 ]. Commonly used receptors for brain targeting with liposomes are insulin, glucose, transferrin, l–type amino acid transporter-1, low-density lipoproteins, folate–receptors, etc.…”

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

“…They act as a vehicle for intercellular communication and transport and are involved in synaptic plasticity, glutamate uptake, neuroprotection, and may promote axonal transport and modulate neuroinflammation [ 34 , 42 , 43 ]. EVs can overcome the blood-brain barrier (BBB) and enter the blood stream, particularly in neurodegenerative diseases and neuroinflammation, accompanied by BBB disruption [ 32 , 44 , 45 , 46 ].…”