Abstract
Persistent cardiac hypertrophy causes heart failure and sudden death. Gene therapy is a promising intervention for this disease, but is limited by the lack of effective delivery systems. Herein, it is reported that CHO‐PGEA (cholesterol (CHO)‐terminated ethanolamine‐aminated poly(glycidyl methacrylate)) can efficiently condense small RNAs into nanosystems for preventing cardiac hypertrophy. CHO‐PGEA contains two features: 1) lipophilic cholesterol groups enhance transfection efficiency in cardiomyocytes, 2) abundant hydrophilic hydroxyl groups benefit biocompatibility. miR‐182, which is known to downregulate forkhead box O3, is selected as an intervention target and can be blocked by synthetic small RNA inhibitor of miR‐182 (miR‐182‐in). CHO‐PGEA can efficiently deliver miR‐182‐in into hearts. In the mice with aortic coarctation, CHO‐PEGA/miR‐182‐in significantly suppresses cardiac hypertrophy without organ injury. This work demonstrates that CHO‐PGEA/miRNA nanosystems are very promising for RNA‐based therapeutics to treat heart diseases.
Highlights
Introduction sion, which is upregulated inCMs of hypertrophic mouse heart or heart tissues of patients with heart failure.[8,9] It is interestingCardiovascular disease (CVD) remains the major cause of mor- to evaluate whether the manipulation of specific miRNAs such as bidity and mortality
For the preparation of CHO-PGEA/miRNA nanoparticles, CHO-PGEA consisting of cholesterol and low-toxic PGEA was prepared based on CHO-terminated poly(glycidyl methacrylate) (CHO-PGMA, Mn = 9.25 × 103 g mol−1) as reported before.[16]
Our results demonstrated that CHO-PGEA/miR-182-in complex could block cardiac hypertrophy induced by pressure overload, improve cardiac function
Summary
Effective capacity to condense nucleic acid is prerequisite for a good gene vector, which was evaluated by agarose gel electrophoresis, dynamic light scattering, ζ-potential and atomic force microscope (AFM) imaging. Gold-standard PEI (25 kDa) was tested for comparison.[19]. Both of CHO-PGEA and PEI could completely condense miRNA when the N/P ratio reached to 2. The particle sizes and ζ-potentials of CHO-PGEA/miRNA and PEI/miRNA complexes at various N/P ratios were measured by dynamic light scattering (DLS) (Figure 2B). The particle sizes of all the complexes ranged from 150–250 nm at various N/P ratios with good distribution (Table S1, Supporting Information). The above results illustrated that miRNA could be effectively condensed by CHO-PGEA and PEI.
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