Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

Abstract

Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals. The naïve macrophage (Mϕ) exosomes can utilize, 1) on the one hand, the integrin lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), and, 2) on the other hand, the carbohydrate-binding C-type lectin receptors, to interact with brain microvessel endothelial cells comprising the BBB. Notably, upregulation of ICAM-1, a common process in inflammation, promotes Mϕ exosomes uptake in the BBB cells. We further demonstrate in vivo that naïve Mϕ exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein, the brain derived neurotrophic factor (BDNF), to the brain. This delivery is enhanced in the presence of brain inflammation, a condition often present in CNS diseases. Taken together, the findings are of interest to basic science and possible use of Mϕ-derived exosomes as nanocarriers for brain delivery of therapeutic proteins to treat CNS diseases.

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

“…Notably, upregulation of ICAM-1, a common process in inflammation, promoted M/ EVs' uptake by BBB. By means of this, naïve M/ exosomes, after intravenous administration, could cross the BBB and deliver the brain-derived neurotrophic factor (BDNF), into brain (Yuan et al, 2017). Similarly, Haney et al (2015) reported earlier that macrophage-derived exosomes loaded with catalase can be considerably detected in brain of mouse with Parkinson's disease following intranasal administration.…”

“…The naïve macrophage (M/) EVs can penetrate through the BBB in mammals. The mechanism might be that these EVs contain integrin lymphocyte function-associated antigen 1 (LFA-1), intercellular adhesion molecule 1 (ICAM-1) (Jin et al, 2018), and carbohydrate-binding C-type lectin receptors (Aranda-Souza et al, 2019), that can interact with brain vessel endothelial cells comprising the BBB (Yuan et al, 2017). Notably, upregulation of ICAM-1, a common process in inflammation, promoted M/ EVs' uptake by BBB.…”

Biocompatible bacteria-derived vesicles show inherent antimicrobial activity

“…Extracellular vesicles (EVs) are small phospholipid based nanoparticles decorated with membrane and surface proteins and they are thought to be involved in cell-to-cell transfer of information [16,17]. EVs are currently explored for potential therapy of different applications ranging from cancer therapy [18], inflammation [19], gene delivery [20] and to fighting infections [21] because of their natural composition and inherent targeting properties [22]. Nevertheless, ongoing limitations of EVs include issues of upscale production in a biotechnologically controllable manner and post-processing regarding loading and modification for targeted tissue interaction [23] which may overall compromise their applicability in clinical trials.…”

A new temperature-dependent strategy to modulate the epidermal growth factor receptor

“…Temperature modulation is a common and powerful research strategy to block temperaturedependent processes, such as endocytosis [38–42]. While cold-incubation is not specific for a particular mechanism of endocytosis, it is used widely in research community to nonspecifically block all endocytosis.…”