Journal
ADVANCED SCIENCE
Volume 6, Issue 5, Pages -Publisher
WILEY
DOI: 10.1002/advs.201801809
Keywords
hepatic stellate cells; liver fibrosis; miRNA delivery; magnetic resonance imaging visibility; nanomedicine; synergistic therapy
Categories
Funding
- National Natural Science Foundation of China [U1501243, 21875289, 31530023, U1401242, 51373203, 81271562]
- National Basic Research Program of China [2015CB755500]
- National Key R&D Program of China [2016YFE0117100]
- Natural Science Foundation of the Guangdong Province [2014A030312018, 2016A030313554, 2015A030313283]
- Guangdong Innovative and Entrepreneurial Research Team Program [2013S086]
- Guangdong-Hong Kong Joint Innovation Project [2016A050503026]
- Project on the Integration of Industry, Education and Research of Guangdong Province [2013B090500094]
- Major Project on the Integration of Industry, Education and Research of Guangzhou City [201704030123]
- Science and Technology Program of Guangzhou [201704020016]
- Fundamental Research Funds for the Central Universities [16lgjc59, 20162900031650004]
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Liver fibrosis, as one of the leading causes of liver-related morbidity and mortality, has no Food and Drug Administration (FDA)-approved antifibrotic therapy yet. Although microRNA-29b (miRNA-29b) and microRNA-122 (miRNA-122) have great potential in treating liver fibrosis via regulating profibrotic genes in hepatic stellate cells (HSCs), it is still a challenge to achieve a HSC-targeted and meanwhile noninvasively trackable delivery of miRNAs in vivo. Herein, a pH-sensitive and vitamin A (VA)-conjugated copolymer VA-polyethylene glycol-polyethyleneimine-poly(N-(N',N'-diisopropylaminoethyl)-co-benzylamino) aspartamide (T-PBP) is synthesized and assembled into superparamagnetic iron oxide (SPIO)-decorated cationic micelle for miRNA delivery. The T-PBP micelle efficiently transports the miRNA-29b and miRNA-122 to HSC in a magnetic resonance imaging-visible manner, resulting in a synergistic antifibrosis effect via downregulating the expression of fibrosis-related genes, including collagen type I alpha 1, alpha-smooth muscle actin, and tissue inhibitor of metalloproteinase 1. Consequently, the HSC-targeted combination therapy with miRNA-29b and miRNA-122 demonstrates a prominent antifibrotic efficacy in terms of improving liver function and relieving hepatic fibrosis.
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