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Biological Activity Of miRNA-27a Using Peptide-based Drug Delivery Systems
Anna-Laurence Schachner-Nedherer1, Oliver Werzer1, Karin Kornmueller2
1Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, University of Graz, Graz 8010, Austria.
Background:
Endogenously expressed microRNAs (miRNAs) have attracted attention as important regulators in post-transcriptionally controlling gene expression of various physiological processes. As miRNA dysregulation is often associated with various disease patterns, such as obesity, miRNA-27a might therefore be a promising candidate for miRNA mimic replacement therapy by inhibiting adipogenic marker genes. However, application of naked nucleic acids faces some limitations concerning poor enzymatic stability, bio-membrane permeation and cellular uptake. To overcome these obstacles, the development of appropriate drug delivery systems (DDS) for miRNAs is of paramount importance.
Methods:
In this work, a triple combination of atomic force microscopy (AFM), brightfield (BF) and fluorescence microscopy was used to trace the cellular adhesion of N-TER peptide-nucleic acid complexes followed by time-dependent uptake studies using confocal laser scanning microscopy (cLSM). To reveal the biological effect of miRNA-27a on adipocyte development after transfection treatment, Oil-Red-O (ORO)- staining was performed to estimate the degree of in lipid droplets accumulated ORO in mature adipocytes by using light microscopy images as well as absorbance measurements.
Results:
The present findings demonstrated that amphipathic N-TER peptides represent a suitable DDS for miRNAs by promoting non-covalent complexation through electrostatic interactions between both components as well as cellular adhesion of the N-TER peptide - nucleic acid complexes followed by uptake across cell membranes and intracellular release of miRNAs. The anti-adipogenic effect of miRNA-27a in 3T3-L1 cells could be detected in mature adipocytes by reduced lipid droplet formation.
Conclusion:
The present DDS assembled from amphipathic N-TER peptides and miRNAs is capable of inducing the anti-adipogenic effect of miRNA-27a by reducing lipid droplet accumulation in mature adipocytes. With respect to miRNA mimic replacement therapies, this approach might provide new therapeutic strategies to prevent or treat obesity and obesity-related disorders.
Insights
N-TER peptide drug delivery systems effectively deliver miRNA-27a to inhibit fat accumulation in adipocytes. This approach shows promise for treating obesity and related disorders through miRNA mimic replacement therapy.
Area of Science:
- Biochemistry and Molecular Biology
- Biotechnology
- Cell Biology
Background:
- MicroRNAs (miRNAs) regulate gene expression and are implicated in diseases like obesity.
- miRNA-27a shows potential for inhibiting adipogenic genes, but naked nucleic acids have delivery challenges.
- Developing effective drug delivery systems (DDS) for miRNAs is crucial for therapeutic applications.
Purpose of the Study:
- To develop and evaluate a novel drug delivery system (DDS) for miRNA-27a.
- To investigate the anti-adipogenic effects of miRNA-27a delivered via the N-TER peptide DDS.
- To assess the potential of this approach for obesity treatment.
Main Methods:
- Utilized a combination of atomic force microscopy (AFM), brightfield (BF), and fluorescence microscopy to study N-TER peptide-nucleic acid complex interactions.
- Employed confocal laser scanning microscopy (cLSM) for time-dependent cellular uptake studies.
- Assessed anti-adipogenic effects using Oil-Red-O (ORO) staining and absorbance measurements in 3T3-L1 adipocytes.
Main Results:
- Amphipathic N-TER peptides formed stable, non-covalent complexes with miRNAs via electrostatic interactions.
- N-TER peptide-nucleic acid complexes demonstrated effective cellular adhesion, uptake, and intracellular miRNA release.
- miRNA-27a delivery via N-TER peptides significantly reduced lipid droplet accumulation in mature adipocytes, indicating an anti-adipogenic effect.
Conclusions:
- The N-TER peptide-based DDS successfully delivered miRNA-27a to induce anti-adipogenic effects in adipocytes.
- This DDS approach offers a promising strategy for miRNA mimic replacement therapy.
- The findings suggest potential therapeutic applications for preventing and treating obesity and associated disorders.
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