Drug resistance reversal by interventing cancer bioenergetics with spherical helical polypeptide-potented gene silencing

Abstract Drug resistance diminishes the efficacies of anticancer therapeutics and causes the failure of clinical cancer chemotherapy. Herein, we reported a promising strategy to reverse drug resistance via RNA interference (RNAi)-assisted intervention of cancer bioenergetics. Densely packed, guanidine-rich, spherical helical polypeptide (DPP) was developed to encapsulate doxorubicin (DOX) inside its hydrophobic cavity and form polyelectrolyte nanocomplexes (NCs) with PKM2 siRNA. The NCs were further surface-decorated with hyaluronic acid (HA) to enhance the serum stability and promote tumor targeting via binding to over-expressed CD44 on cancer cell membranes. DPP with multivalent topology mediated potent trans-membrane delivery of PKM2 siRNA into DOX-resistance cancer cells. PKM2 down-regulation suppressed the glycolysis metabolism and depleted energy supply for ATP-binding cassette (ABC) transporters, thus inhibiting drug efflux to reverse drug resistance. Meanwhile, PKM2 silencing starved tumor cells, induced intracellular reactive oxygen species (ROS) generation, and triggered mitochondrial collapse, which aggravated cell apoptosis to achieve potent and cooperative anti-cancer effect with chemotherapy. This study thus provides an effective topology-controlled approach for designing trans-membrane siRNA delivery vehicles, and it also renders a promising tool in rejuvenating chemotherapy against drug-resistant tumors via a unique anti-bioenergetics mechanism.