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

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

  • ACS Appl Mater Interfaces. 2023 Jun 24. doi: 10.1021/acsami.3c05007.
Guolin Zhao 1 2,  William Ho 3,  Jinxian Chu 1 2,  Xiaojian Xiong 1 2,  Bin Hu 1 2,  Kofi Oti Boakye-Yiadom 1 2,  Xiaoyang Xu 3 4,  Xue-Qing Zhang 1 2
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
  • 2 National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, New Jersey 07102, United States.
  • 4 Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, New Jersey 07102, United States.
PMID: 37354089 DOI: 10.1021/acsami.3c05007
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.

Keywords

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

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