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 down-regulate 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.