Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

Abstract

Nowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50–100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.

A Historical Review of Brain Drug Delivery

“…The lack of success in brain drug delivery with stem cells has led to the development of exosomes as a brain drug delivery vehicle [295,296]. Exosomes are naturally occurring extracellular vesicles, which are released from the plasma membrane of cells, and may be taken up by neighboring cells.…”

Interplay between exosomes and autophagy machinery in pain management: State of the art

“…Beyond these mechanisms, some reports demonstrate the existence of the ESCRT-independent pathway in the biogenesis of MVBs, which were confirmed after the suppression of four main subunits of the ESCRT complex ( Juan and Fürthauer, 2018 ). In support of this notion, it has been shown that the release of Exo in mouse oligodendrocytes is an ESCRT-free mechanism via the activity of ceramide-generating enzyme neutral sphingomyelinases (nSMase) ( Heidarzadeh et al, 2021 ). Tetraspanins, as intracellular effectors, partake in the biogenesis of Exo and cargo sorting ( Chairoungdua et al, 2010 ).…”

“…These features show that Exo are the key regulators during physiological and pathological conditions with specific factors that give us valuable data about the status and intensity of pathologies. Because Exo can easily distribute in the systemic circulation, studying exosomal profiles in blood samples is helpful in the determination of pain-related factors ( Heidarzadeh et al, 2021 ). Despite the existence of a blood–brain barrier with selective permeability, Exo can engage several strategies to cross this natural barrier from the brain to the blood side and vice versa ( van Dijk et al, 2010 ).…”

Biological Features of Extracellular Vesicles and Challenges

“…Overall, EVs possess ability to actively penetrate biological barriers. Although the underlying mechanism remains unclear (Heidarzadeh et al, 2021) and how to control the penetration of EVs in biological barriers remains a mystery, EVs are promising to be used as drug delivery vehicles for central nervous system diseases. Noteworthy, abnormal cell-derived EVs should be removed to avoid cancer risk.…”