Inhalable siRNA Nanoparticles for Enhanced Tumor-Targeting Treatment of KRAS-Mutant Non-Small-Cell Lung Cancer

Kirsten rat sarcoma (KRAS) isthe most commonly mutated oncogene in lung cancers. Gene therapy isemerging as a promising cancer treatment modality; however, the systemicadministration of gene therapy has been limited by inefficient deliveryto the lungs and systemic toxicity. Herein, we report a noninvasiveaerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutantnon-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity duringnebulization, with preferential distribution within the tumor-bearinglung. Inhalable siKRAS@GCLPP NPs show not only significanttumor-targeting capability but also enhanced antitumor activity inan orthotopic mouse model of human KRAS-mutant NSCLC.The nebulized delivery of siKRAS@GCLPP NPs demonstratespotent knockdown of mutated KRAS in tumor-bearinglungs without causing any observable adverse effects, exhibiting abetter biosafety profile than the systemic delivery approach. Theresults present a promising inhaled gene therapy approach for thetreatment of KRAS-mutant NSCLC and other respiratorydiseases.