# Targeted drug delivery via CNS cell specific exosomes in neurodegenerative diseases

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $194,375

## Abstract

Summary
Progressive and fatal neurodegenerative disorders, including Alzheimer disease (AD) and Parkinson
disease (PD), represent a huge unmet need for treatment. The low efficacy of current treatment
methods is partially due to the presence of various obstacles in the delivery routes, with the blood–
brain barrier (BBB) being the main barrier of drug delivery to the brain. In order to develop effective
therapies for these disorders, efficient and safe drug delivery systems to cross the BBB are needed.
Promising results have been obtained by using synthetic nanoparticles or liposomes as drug carriers,
but these systems still face challenges such as immune activation mediated rapid clearance of the
vehicle and concomitant decrease in efficacy when re-administered. To overcome the limitations,
researchers in recent studies have developed targeted systems that use self-derived exosomes, the
membrane vesicles secreted by most cell types and act as carriers of biomolecules between cells, for
nucleic acid or protein delivery to the brain, and demonstrated their beneficial properties and
efficiency in animal models of neurodegenerative diseases, though the targeting doesn't seem to be
cell type or system specific. In this study, based on our recent findings on central nervous system
(CNS) cell-type specific exosomes, we propose to further develop exosome-based but more efficient
and functional specific delivering systems. Specifically, our previous studies have demonstrated that
red blood cell (RBC)-derived exosomes/microvesicles could cross the BBB, particularly under
inflammatory conditions, and that exosomes carrying CNS cell specific surface markers (e.g., L1CAM
for neurons and CNPase for oligodendrocytes) could be transported from the brain into peripheral
blood and re-enter the brain readily even without peripheral inflammation. Therefore, we hypothesize
that exosomes derived from hematopoietic stem cells (HSCs)/RBC progenitors, when modified to
express brain cell-specific surface markers, can cross the BBB from peripheral blood more efficiently
and deliver nucleic acid or protein cargos into the target brain cells more specifically. In this study, we
will first develop such exosomal delivery systems by engineering cultured human or mouse HSCs to
express brain cell-specific surface markers, with or without additional previously identified strategies
to enhance transportation efficiency and stability, and verify the cellular uptake and BBB crossing of
the modified exosomes in in vitro and in vivo models. We also plan to engineer exosomes to carry
additional surface markers to target more specific neuronal subpopulations, and finally test the
delivery of potential treatments in neurodegenerative disease animal models. This proposed study will
likely develop a more efficient and targeted drug delivery system for neurodegenerative diseases, and
provide the foundation for future studies of effective and targeted treatments.

## Key facts

- **NIH application ID:** 10000002
- **Project number:** 5R21AG060142-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Min Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000002

## Citation

> US National Institutes of Health, RePORTER application 10000002, Targeted drug delivery via CNS cell specific exosomes in neurodegenerative diseases (5R21AG060142-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000002. Licensed CC0.

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