Extracellular Vesicles as Tools for Crossing the Blood-Brain Barrier to Treat Lysosomal Storage Diseases

Abstract

Extracellular vesicles (EVs) are nanosized, membrane-bound structures that have emerged as promising tools for drug delivery, especially in the treatment of lysosomal storage disorders (LSDs) with central nervous system (CNS) involvement. This review highlights the unique properties of EVs, such as their biocompatibility, capacity to cross the blood-brain barrier (BBB), and potential for therapeutic cargo loading, including that of enzymes and genetic material. Current therapies for LSDs, like enzyme replacement therapy (ERT), often fail to address neurological symptoms due to their inability to cross the BBB. EVs offer a viable alternative, allowing for targeted delivery to the CNS and improving therapeutic outcomes. We discuss recent advancements in the engineering and modification of EVs to enhance targeting, circulation time and cargo stability, and provide a detailed overview of their application in LSDs, such as Gaucher and Fabry diseases, and Sanfilippo syndrome. Despite their potential, challenges remain in scaling production, ensuring isolation purity, and meeting regulatory requirements. Future developments will focus on overcoming these barriers, paving the way for the clinical translation of EV-based therapies in LSDs and other CNS disorders.

Keywords: blood–brain barrier; drug delivery; enzyme replacement therapy; exosomes; extracellular vesicles; lysosomal storage diseases; neurodegenerative diseases; protein delivery.

Figure 1

Multisystemic manifestations of lysosomal storage disorders (LSDs). Main disorders showing manifestations in various organs and tissues are indicated. The image does not aim to list all the manifestations of all the diseases, but instead, give an idea of the multisystemic nature of the LSDs.

Figure 2

Timeline for the approval of LSD-specific therapies. For the sake of clarity, stem cell transplantation has not been included. Therapies: ERT—enzyme replacement therapy; SRT—substrate reduction therapy; CT—chaperone therapy; GT—gene therapy. Diseases: GD—Gaucher disease; FD—Fabry disease; MPS—mucopolysaccharidosis; NPC—Niemann–Pick type C; LAL-D—lysosomal acid lipase deficiency; ASMD—acid sphingomyelinase deficiency; CLN2; AM—alpha mannosidosis; MLD—metachromatic leukodystrophy. For the sake of clarity, stem cell transplantation has not been included in the scheme.

Figure 3

Scheme of the loading strategies and the surface modification possibilities in engineered EVs.

Figure 4

Different mechanisms of crossing the BBB by EVs. Transcellular mechanisms include macropinocytosis, adsorptive-mediated endocytosis, clathrin-mediated endocytosis and caveolin-mediated endocytosis, and imply that EVs cross the endothelial cell to be excreted by exocytosis. Paracellular mechanisms, by contrast, involve EVs moving through tight junctions between endothelial cells.