Abstract
There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a key role in fibroblast activation and that knocking down MRTF can lead to reduced scarring and fibrosis. Here, we have developed a receptor-targeted liposome-peptide-siRNA nanoparticle as a non-viral delivery system for MRTF-B siRNA in conjunctival fibrosis. Using 50 nM siRNA, the MRTF-B gene was efficiently silenced by 76% and 72% with LYR and LER nanoparticles, respectively. The silencing efficiency was low when non-targeting peptides or siRNA alone or liposome-siRNA alone were used. LYR and LER nanoparticles also showed higher silencing efficiency than PEGylated LYR-P and LER-P nanoparticles. The nanoparticles were not cytotoxic using different liposomes, targeting peptides, and 50 nM siRNA. Three-dimensional fibroblast-populated collagen matrices were also used as a functional assay to measure contraction in vitro, and showed that MRTF-B LYR nanoparticles completely blocked matrix contraction after a single transfection treatment. In conclusion, this is the first study to develop and show that receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient and safe non-viral siRNA delivery system that could be used to prevent fibrosis after glaucoma filtration surgery and other contractile scarring conditions in the eye.
Highlights
There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a key role in fibroblast activation and that knocking down MRTF can lead to reduced scarring and fibrosis[14,15,16]
We have developed receptor-targeted liposome-peptide-Small interfering RNAs (siRNAs) nanoparticles as an efficient non-viral delivery system for MRTF-B siRNAs in human Tenon’s fibroblasts to prevent post-surgical fibrosis after glaucoma filtration surgery and other fibroblast-induced contractile scarring conditions in the eye
Fibrosis remains a critical determinant of the long-term surgical success after glaucoma filtration surgery and small molecule therapeutics hold a lot of potential to modulate post-surgical wound healing in the eye[32]
Summary
There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a key role in fibroblast activation and that knocking down MRTF can lead to reduced scarring and fibrosis[14,15,16]. We have developed PEGylated formulations to further increase the receptor-targeted specificity and transfection efficiency in cells and to enable better biocompatibility of the nanocomplexes[25,26]. We have developed receptor-targeted liposome-peptide-siRNA nanoparticles as an efficient non-viral delivery system for MRTF-B siRNAs in human Tenon’s fibroblasts to prevent post-surgical fibrosis after glaucoma filtration surgery and other fibroblast-induced contractile scarring conditions in the eye
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