TY - JOUR
T1 - Inhalable siRNA Nanoparticles for Enhanced Tumor-Targeting Treatment of KRAS-Mutant Non-Small-Cell Lung Cancer
AU - Zhao, Guolin
AU - Ho, William
AU - Chu, Jinxian
AU - Xiong, Xiaojian
AU - Hu, Bin
AU - Boakye-Yiadom, Kofi Oti
AU - Xu, Xiaoyang
AU - Zhang, Xue Qing
N1 - Funding Information:
X.-Q.Z. acknowledges funding from the “Open Competition to Select the Best Candidates” Key Technology Program for Nucleic Acid Drugs of NCTIB (Grant No. NCTIB2022HS02002), the Natural Science Foundation of Shanghai (23ZR1427600), Shanghai Jiao Tong University Scientific and Technological Innovation Funds (2019TPA10), Foundation of National Facility for Translational Medicine (Shanghai) (TMSK-2020-008), and the Interdisciplinary Program of Shanghai Jiao Tong University [project number ZH2018ZDA36 (19X190020006)]. X.Xu acknowledges support from the National Science Foundation (2001606), and the Gustavus and Louise Pfeiffer Research Foundation Award.
Publisher Copyright:
© 2023 American Chemical Society
PY - 2023/7/5
Y1 - 2023/7/5
N2 - 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.
AB - 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.
KW - KRAS mutation
KW - inhaled siRNA therapeutics
KW - lung cancer therapy
KW - pulmonary nucleic acid delivery
KW - tumor-targeting gene therapy
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U2 - 10.1021/acsami.3c05007
DO - 10.1021/acsami.3c05007
M3 - Article
C2 - 37354089
AN - SCOPUS:85164243797
SN - 1944-8244
VL - 15
SP - 31273
EP - 31284
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 26
ER -