Abstract: Nanoparticles containing an aqueous core containing one or more nucleic acids, such as siRNA, and a shell containing one or more hydrophobic cationic materials, one or more amphiphilic materials, and one or more therapeutic, diagnostic, and/or prophylactic agents are. The hydrophobic cationic material and the hydrophobic portion of the amphiphilic material provide a non-polar polymer matrix for loading non-polar drugs, protect and promoting siRNA molecule retention inside the NP core, and control drug release. The hydrophilic portion of the amphiphilic material can form a corona around the particle which prolongs circulation of the particles in the blood stream and decreases uptake by the RES.