Disclosed herein are compositions comprising nanoparticles comprising a carrier polypeptide and a double-stranded oligonucleotide, wherein the carrier polypeptide comprises a cell-targeting segment, a cell-penetrating segment, and an oligonucleotide-binding segment: and wherein the molar ratio of the carrier polypeptide to the double-stranded oligonucleotide in the nanoparticle composition is less than about 6:1, along with methods of making and using such nanoparticles. Further described are methods of treating a subject with a cancer, such as a chemotherapeutic drug resistant cancer comprising administering to the subject a composition comprising nanoparticles, the nanoparticles comprising a carrier polypeptide comprising a cell-targeting segment, a cell-penetrating segment, and an oligonucleotide-binding segment； a double-stranded oligonucleotide bound to the oligonucleotide-binding segment； and a chemotherapeutic drug bound to the double-stranded oligonucleotide. Also described are pharmaceutical compositions, articles of manufacture, and kits comprising the described nanoparticles.
