Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System
The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods....
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/16/1/102 |
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| author | Mena Asha Krishnan Olawale A. Alimi Tianshu Pan Mitchell Kuss Zeljka Korade Guoku Hu Bo Liu Bin Duan |
| author_facet | Mena Asha Krishnan Olawale A. Alimi Tianshu Pan Mitchell Kuss Zeljka Korade Guoku Hu Bo Liu Bin Duan |
| author_sort | Mena Asha Krishnan |
| collection | DOAJ |
| description | The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies. |
| first_indexed | 2024-03-08T10:37:31Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-08T10:37:31Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-73a7109c4b2646c38f89400bede28ebd2024-01-26T18:07:34ZengMDPI AGPharmaceutics1999-49232024-01-0116110210.3390/pharmaceutics16010102Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous SystemMena Asha Krishnan0Olawale A. Alimi1Tianshu Pan2Mitchell Kuss3Zeljka Korade4Guoku Hu5Bo Liu6Bin Duan7Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USAMary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USAMary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USAMary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USAMary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USAMary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USAThe administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies.https://www.mdpi.com/1999-4923/16/1/102red blood cellstetanus toxin-C fragmentclick chemistrytarget deliveryperipheral nerve injury |
| spellingShingle | Mena Asha Krishnan Olawale A. Alimi Tianshu Pan Mitchell Kuss Zeljka Korade Guoku Hu Bo Liu Bin Duan Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System Pharmaceutics red blood cells tetanus toxin-C fragment click chemistry target delivery peripheral nerve injury |
| title | Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System |
| title_full | Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System |
| title_fullStr | Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System |
| title_full_unstemmed | Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System |
| title_short | Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System |
| title_sort | engineering neurotoxin functionalized exosomes for targeted delivery to the peripheral nervous system |
| topic | red blood cells tetanus toxin-C fragment click chemistry target delivery peripheral nerve injury |
| url | https://www.mdpi.com/1999-4923/16/1/102 |
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