Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System

Mena Asha Krishnan, Olawale A. Alimi, Tianshu Pan, Mitchell Kuss, Zeljka Korade, Guoku Hu, Bo Liu, Bin Duan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number102
JournalPharmaceutics
Volume16
Issue number1
DOIs
StatePublished - Jan 2024

Keywords

  • click chemistry
  • peripheral nerve injury
  • red blood cells
  • target delivery
  • tetanus toxin-C fragment

ASJC Scopus subject areas

  • Pharmaceutical Science

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