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

Guolin Zhao, William Ho, Jinxian Chu, Xiaojian Xiong, Bin Hu, Kofi Oti Boakye-Yiadom, Xiaoyang Xu, Xue Qing Zhang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Kirsten rat sarcoma (KRAS) 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 “siKRAS@GCLPP NPs,” to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS 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 KRAS-mutant NSCLC and other respiratory diseases.

Original languageEnglish (US)
Pages (from-to)31273-31284
Number of pages12
JournalACS Applied Materials and Interfaces
Volume15
Issue number26
DOIs
StatePublished - Jul 5 2023

All Science Journal Classification (ASJC) codes

  • General Materials Science

Keywords

  • KRAS mutation
  • inhaled siRNA therapeutics
  • lung cancer therapy
  • pulmonary nucleic acid delivery
  • tumor-targeting gene therapy

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