Ultrasound Assisted Exosomal Delivery of Tissue Responsive mRNA for Enhanced Efficacy and Minimized Off-Target Effects
Open accessAbstract
Exosome-mediated nucleic acids delivery has been emerging as a promising strategy for gene therapy. However, the intrinsic off-target effects due to non-specific uptake of exosomes by other tissues remain the big hurdle for clinical application. In this study, we aimed to enhance the efficacy and minimize the off-target effects by simultaneously encapsulating engineered mRNA translationally activated by tissue-specific microRNA (miRNA) and increasing targeted delivery efficiency via ultrasound-targeted microbubble destruction (UTMD). Briefly, the upstream of interest transcript was engineered to harbor an internal ribosome entry site (IRES) modified with two miRNA recognition sites. In vitro reporter experiments revealed that the engineered mRNA could be encapsulated into exosomes and can be translationally activated by corresponding miRNAs in the recipient cells. By a proof-of-principle in vivo experiment, we encapsulated miR-148a (an adipose relatively specific miRNA)-responsive PGC1α mRNA into exosomes and delivered the exosomes into the adipose tissue with the aid of UTMD. Efficient PGC1α translation was activated in the adipose tissue, together with obvious browning induction. Moreover, there was much lower off-target translation of PGC1 α in lungs and other tissues. Taken together, our study establishes a novel adipose-specific exosome delivery strategy to enhance efficacy and minimize off-target effects simultaneously.
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This method effectively enhanced expression of PGC1α protein, particularly in mouse adipose tissue, while reducing expression in other tissues such as lung.
“This method effectively enhanced the expression of PGC1α protein, particularly in mouse adipose tissue, while reducing expression in other tissues such as the lung.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [121]
Exosomes utilized to transport PGC1α mRNA, responsive to miR-148a and specific to adipose tissue, achieved successful delivery to targeted adipose tissue through ultrasound-guided microvesicle disruption.
“Exosomes were utilized to transport PGC1α mRNA, which is responsive to miR-148a and specific to adipose tissue. Through microvesicle disruption guided by ultrasound, the system achieved successful delivery to the targeted adipose tissue.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [121]
Overall therapeutic effect was improved while minimizing unintended effects on non-target tissues.
“As a result, the overall therapeutic effect was improved while minimizing unintended effects on non-target tissues (Fig. 6) [121].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [121]
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- Authors
- Sun, W., Xing, C., Zhao, L., Zhao, P., Yang, G., & Yuan, L.
- Affiliations
- Tang Du Hospital (CN)
- Air Force Medical University (CN)
- Corresponding author
- Yang, Guodong
- Yuan, Lijun
- Venue
- Molecular Therapy Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 20
- Pages
- 558-567
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC7182664
- OpenAlex
- W3015494845
- Cited by
- 62
- References
- 36
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 9 · 2021: 7 · 2020: 2
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (31771507, 81671690, 81871357, 81970737)
- Fourth Military Medical University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- ultrasound-targeted microbubble destruction, internal ribosome entry site, PGC-1α, miR-148a, brown adipose tissue browning, off-target effects, gene therapy
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