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

 

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

by

Hojun Choi

¹,

Kyungsun Choi

¹,

Dae-Hwan Kim

¹,

Byung-Koo Oh

¹,

Hwayoung Yim

¹,

Soojin Jo

¹ and

Chulhee Choi

^1,2,*

¹

ILIAS Biologics Inc., Daejeon 34014, Korea

²

Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea

^*

Author to whom correspondence should be addressed.

Academic Editors: Vibhuti Agrahari, Prashant Kumar and Maria Carafa

Pharmaceutics 2022, 14(3), 672; https://doi.org/10.3390/pharmaceutics14030672

Received: 25 December 2021 / Revised: 10 March 2022 / Accepted: 16 March 2022 / Published: 18 March 2022

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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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.

Keywords: exosome; brain delivery; BBB crossing; transcytosis

1. Introduction

The central nervous system (CNS) is one of the most in-demand areas for the development of new therapeutics owing to the increasing occurrence rate of neurodegenerative disorders. However, it remains the most difficult area for drug development because of the blood–brain barrier (BBB), which prevents most of the currently developed drugs from entering the brain parenchyma. The BBB functions as a tight barrier to protect the CNS from potential neurotoxic substances, and regulates the selective transport of specific molecules and nutrients to maintain CNS homeostasis. Water molecules and small ions cross brain capillaries through channels, and small molecules under 500 Da can cross the BBB via passive diffusion [1]. However, macromolecules require specific receptors or transport proteins to facilitate receptor- or adsorptive-mediated transport for entry into the brain parenchyma. The increasing need for new therapeutics for CNS diseases has prompted the investigation of various endogenous transportation mechanisms that can deliver macromolecules across the BBB. The development of novel therapeutics utilizing these transportation pathways has been actively validated in numerous preclinical and clinical studies.

Among the novel therapeutics, exosomes have recently gained attention because of their role as therapeutic vehicles for delivering various active pharmaceutical ingredients to the brain. Exosomes, or small extracellular vesicles (EVs), are a subtype of EVs defined as single-membrane lipid bilayer vesicles generated by vesicle budding into endosomes that mature into multivesicular bodies or by direct vesicle budding from the plasma membrane [2]. Different subtypes of EVs have been identified based on their size and density, which allows separation by methods such as tangential flow filtration, size exclusion chromatography, and differential centrifugation [3]. Nevertheless, careful interpretation is necessary when analyzing different groups of EVs because most EV purification methods cannot determine EVs based on their biogenesis pathways, but rather isolate subtypes of EVs based on their physical properties. Among EVs, exosomes are natural nanoparticles with low immunogenicity that can deliver diverse biological molecules, such as nucleic acids, proteins, lipids, and carbohydrates to target cells [4]. Compared with cell therapy, exosomes possess similar therapeutic efficacy with improved safety profiles in various diseases, such as cancer and ischemia [5,6,7,8,9,10]. To induce targeted delivery to the brain, therapeutic exosomes can be engineered to express various targeting moieties via direct modification methods, such as chemical modification of exosomal surfaces, or indirect modification methods via genetic engineering of exosome-producing cells. The aim of this review is to briefly discuss current engineering strategies for delivering therapeutics across the BBB and highlight recent advances in the targeted delivery of exosomes to the brain.

 

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