Polymeric transfection reagents for delivery of nucleic acids to cells, pharmaceutical compositions comprising same, and methods of preparing and using same are provided. A compound comprises polyethylenimine, a lipid selected from cholesterol, lauric acid, palmitic acid, or stearic acid, and optionally, a histidine. A nanoparticle comprises the compound complexed to a nucleic acid. A composition or pharmaceutical composition comprises the nanoparticle and a pharmaceutically acceptable carrier, anti-fouling agent, targeting ligand, or combinations thereof. A method of treating, preventing, or ameliorating a disease in a subject comprises administering to the subject an effective amount of the nanoparticle or the composition or pharmaceutical composition.
