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Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy
Jia Ke1,2, Jing Ding1, Yichong Xu1
1College of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China. hufq@zju.edu.cn.
Abstract:
Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.
Insights
Engineered microglial exosomes loaded with microRNA-124-3p (Exo-124-3p) effectively cross the blood-brain barrier to treat Alzheimer's disease (AD). This novel therapy reduces amyloid plaques and improves cognitive function by targeting the MEKK3/NF-κB pathway.
Area of Science:
- Neuroscience
- Biomedical Engineering
- Molecular Biology
Background:
- Alzheimer's disease (AD) treatment is hindered by single-target therapies and challenges in delivering drugs across the blood-brain barrier (BBB).
- MicroRNA-124-3p (miR-124-3p) shows therapeutic potential for AD, but its delivery to the brain is problematic due to the BBB and instability.
Purpose of the Study:
- To engineer a novel nanomedicine for effective delivery of miR-124-3p to AD-affected brain regions.
- To develop a multifunctional therapeutic approach for Alzheimer's disease using biomimetic nanomedicine.
Main Methods:
- Engineered microglial exosomes enriched with miR-124-3p (Exo-124-3p) for enhanced BBB penetration and microglia targeting.
- Assessed the therapeutic effects of Exo-124-3p on amyloid-beta (Aβ) plaque aggregation, neuroinflammation, and cognitive function in an AD mouse model.
- Investigated the mechanism of action, focusing on the inhibition of the MEKK3/NF-κB signaling pathway.
Main Results:
- Exo-124-3p successfully traversed the BBB and targeted activated microglia.
- Treatment with Exo-124-3p reduced Aβ plaque aggregation, attenuated microglial and astrocyte activation, and demonstrated neuroprotective effects.
- Significant improvement in cognitive function was observed in the AD mouse model treated with Exo-124-3p.
- Exo-124-3p inhibited the MEKK3/NF-κB pathway, ameliorating neuroinflammation.
Conclusions:
- Engineered Exo-124-3p represents a promising biomimetic nanomedicine for multifunctional Alzheimer's disease treatment.
- This approach offers a viable strategy for overcoming BBB delivery challenges for miRNA therapeutics in brain diseases.
- The study provides a new avenue for combinational therapy and miRNA delivery systems for neurological disorders.
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