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

() is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "si@GCLPP NPs," to treat -mutant non-small-cell lung cancer (NSCLC). The self-assembled si@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable si@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human -mutant NSCLC. The nebulized delivery of si@GCLPP NPs demonstrates potent knockdown of mutated in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of -mutant NSCLC and other respiratory diseases.