Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges

Abstract

Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiological barriers highlight their potential as drug carriers. This review provides a comprehensive overview of current strategies to enhance NAD to the brain, focusing on the emerging potential of exosomes as biocompatible and efficient nanocarriers. It synthesizes recent advances in the use of exosomes for NA-BTs in neurological disorders, comparing their advantages with those of conventional nanodelivery systems and cell-based therapies. Additionally, the review highlights innovative exosome engineering approaches to improve brain-targeted delivery, addresses key methodological limitations such as variability in cargo content, and proposes solutions to enhance standardization and safety. Collectively, these insights highlight the translational potential of exosomes and offer a novel perspective on bridging the gap between fundamental research and clinical application.

Keywords: BBB; Exosomes; Neurodegeneration; Neuroinflammation; Neuropharmacology.

Fig. 1

The structure of the neurovascular section. The neurovascular unit (NVU) comprises neurons, glial cells (astrocytes, microglia, oligodendrocytes), and vascular cells (endothelial cells, pericytes, and smooth muscle cells (SMCs)). The NVU’s structure varies along the vascular tree due to differences in the molecular expression of endothelial and mural cells. Endothelial cells form the inner vascular wall at the penetrating arteries, separated from SMCs by the basement membrane. The Virchow–Robin space lies between the pia and the glia limitans. At the arteriolar level, SMCs are organized in a single layer, whereas at the capillary level, pericytes and endothelial cells share a common basement membrane, which is further enveloped by the endfeet of astrocytes. Neurons innervate astrocytes, pericytes, and SMCs. The blood–brain barrier (BBB) is a monolayer of tightly sealed endothelial cells with low permeability, centrally located within the NVU. Cells within the NVU are crucial for angiogenesis, neurogenesis, BBB integrity, cerebral blood flow regulation, extracellular matrix interactions, and neurotransmitter clearance. Source: Adapted from Sweeney et al. [157]

Fig. 2

Summary of nanoparticle-based systems, non-invasive approaches, and targeted delivery (TD) in the brain. A The image illustrates seven key methods for overcoming the blood–brain barrier (BBB): Cell-mediated transcytosis: Immune or stem cells carrying drug payloads traverse the BBB. Carrier-Mediated Transport (CMT): Drugs mimic substrates of transporters like GLUT1 or LAT1 to gain entry. Lipid-Soluble Pathway: Lipophilic drugs diffuse passively through the lipid-rich BBB. Efflux Mechanisms: Strategies to bypass efflux transporters like P-gp, which expel drugs from the brain. Adsorptive-Mediated Transcytosis (AMT): Positively charged carriers interact with endothelial cell surfaces for transport. Paracellular Transport: Temporary BBB disruption enables substances to pass between endothelial cells. Receptor-Mediated Transcytosis (RMT): Drugs conjugated to ligands target receptors like transferrin or low-density lipoprotein receptor (LDLR) to cross the BBB. The titles of parts B and C are demonstrated in the picture. Source: Adapted from Wu et al. [177]

Fig. 3

Overview of different types of extracellular vesicles (EVs). The illustration presents a comprehensive overview of various EVs, emphasizing their structural and functional diversity. Each EV type varies in size, origin, and cargo, offering unique capabilities for therapeutic applications and intercellular communication. Key EV types depicted include: Supermeres and Exomeres: Nanoparticles without lipid bilayer, notable for their unique biomolecular cargo and functions in intercellular communication, metabolic, and signaling processes. Migrasomes: Large vesicles formed during cell migration, playing roles in intercellular signaling and cargo transport. Exosomes: Well-characterized small vesicles derived from the endosomal pathway, crucial for transporting proteins, lipids, and nucleic acids across cells. ARMMs (Arrestin Domain-Containing Protein 1-Mediated Microvesicles): Specialized small vesicles involved in signaling pathways, formed through plasma membrane budding. Ectosomes: A subset of small vesicles with specific size ranges and functional properties. Microvesicles: Larger vesicles formed by direct outward budding of the plasma membrane, involved in cell-to-cell communication and immune modulation. Oncosomes: Large vesicles released from cancer cells, associated with tumor progression and metastasis. Exophers: are formed when cells expel large portions of their cytoplasm, along with cellular components such as organelles, aggregated proteins, and other debris. Source: Adapted from Jeppesen et al. [68]