Cargando…
Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles
Targeted delivery of lysosomal enzymes to the endocytic compartment of human cells represents a transformative technology for treating a large family of lysosomal storage diseases (LSDs). Gaucher disease is one of the most common types of LSDs caused by mutations to the lysosomal β-glucocerebrosidas...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872767/ https://www.ncbi.nlm.nih.gov/pubmed/31754156 http://dx.doi.org/10.1038/s41598-019-53844-5 |
_version_ | 1783472558887141376 |
---|---|
author | Do, Mai Anh Levy, Daniel Brown, Annie Marriott, Gerard Lu, Biao |
author_facet | Do, Mai Anh Levy, Daniel Brown, Annie Marriott, Gerard Lu, Biao |
author_sort | Do, Mai Anh |
collection | PubMed |
description | Targeted delivery of lysosomal enzymes to the endocytic compartment of human cells represents a transformative technology for treating a large family of lysosomal storage diseases (LSDs). Gaucher disease is one of the most common types of LSDs caused by mutations to the lysosomal β-glucocerebrosidase (GBA). Here, we describe a genetic strategy to produce engineered exosomes loaded with GBA in two different spatial configurations for targeted delivery to the endocytic compartment of recipient cells. By fusing human GBA to an exosome-anchoring protein: vesicular stomatitis virus glycoprotein (VSVG), we demonstrate that the chimeric proteins were successfully integrated into exosomes which were secreted as extracellular vesicles (EVs) by producer cells. Isolation and molecular characterization of EVs confirmed that the fusion proteins were loaded onto exosomes without altering their surface markers, particle size or distribution. Further, enzyme-loaded exosomes/EVs added to cultured medium were taken up by recipient cells. Further, the endocytosed exosomes/EVs targeted to endocytic compartments exhibited a significant increase in GBA activity. Together, we have developed a novel method for targeting and delivery of lysosomal enzymes to their natural location: the endocytic compartment of recipient cells. Since exosomes/EVs have an intrinsic ability to cross the blood-brain-barrier, our technology may provide a new approach to treat severe types of LSDs, including Gaucher disease with neurological complications. |
format | Online Article Text |
id | pubmed-6872767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68727672019-12-04 Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles Do, Mai Anh Levy, Daniel Brown, Annie Marriott, Gerard Lu, Biao Sci Rep Article Targeted delivery of lysosomal enzymes to the endocytic compartment of human cells represents a transformative technology for treating a large family of lysosomal storage diseases (LSDs). Gaucher disease is one of the most common types of LSDs caused by mutations to the lysosomal β-glucocerebrosidase (GBA). Here, we describe a genetic strategy to produce engineered exosomes loaded with GBA in two different spatial configurations for targeted delivery to the endocytic compartment of recipient cells. By fusing human GBA to an exosome-anchoring protein: vesicular stomatitis virus glycoprotein (VSVG), we demonstrate that the chimeric proteins were successfully integrated into exosomes which were secreted as extracellular vesicles (EVs) by producer cells. Isolation and molecular characterization of EVs confirmed that the fusion proteins were loaded onto exosomes without altering their surface markers, particle size or distribution. Further, enzyme-loaded exosomes/EVs added to cultured medium were taken up by recipient cells. Further, the endocytosed exosomes/EVs targeted to endocytic compartments exhibited a significant increase in GBA activity. Together, we have developed a novel method for targeting and delivery of lysosomal enzymes to their natural location: the endocytic compartment of recipient cells. Since exosomes/EVs have an intrinsic ability to cross the blood-brain-barrier, our technology may provide a new approach to treat severe types of LSDs, including Gaucher disease with neurological complications. Nature Publishing Group UK 2019-11-21 /pmc/articles/PMC6872767/ /pubmed/31754156 http://dx.doi.org/10.1038/s41598-019-53844-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Do, Mai Anh Levy, Daniel Brown, Annie Marriott, Gerard Lu, Biao Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title | Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title_full | Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title_fullStr | Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title_full_unstemmed | Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title_short | Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
title_sort | targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872767/ https://www.ncbi.nlm.nih.gov/pubmed/31754156 http://dx.doi.org/10.1038/s41598-019-53844-5 |
work_keys_str_mv | AT domaianh targeteddeliveryoflysosomalenzymestotheendocyticcompartmentinhumancellsusingengineeredextracellularvesicles AT levydaniel targeteddeliveryoflysosomalenzymestotheendocyticcompartmentinhumancellsusingengineeredextracellularvesicles AT brownannie targeteddeliveryoflysosomalenzymestotheendocyticcompartmentinhumancellsusingengineeredextracellularvesicles AT marriottgerard targeteddeliveryoflysosomalenzymestotheendocyticcompartmentinhumancellsusingengineeredextracellularvesicles AT lubiao targeteddeliveryoflysosomalenzymestotheendocyticcompartmentinhumancellsusingengineeredextracellularvesicles |