Transcription activator-like effector base editing delivered by a targeted lipid nanoparticle for therapy of lung cancer
Yuling Chen1, Peishan Li1, Ying Xie1
1State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Advanced Pharmaceutical Preparation, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; PKU Medicine-Zhendong Pharmaceutical Joint Laboratory of Advanced Preparation, Health Science Center, Peking University, Beijing, 100191, China.
Abstract:
Lung cancer is the leading cause of cancer-related deaths worldwide. Among them, non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases, while the mutation of KRAS oncogene plays a crucial role in its formation and metastasis. Here, we report a transcription activator-like effector (TALE) base editor that can accurately identify KRAS gene under the guide of TALE and sgRNA, convert C base to T base, thereby generating a stop codon and blocking the expression of KRAS. Besides, a targeted TALE base editing lipid nanoparticle (targeted TALE LNP) is developed by rationally designing with cancer-targeted EGFR peptide. The targeted TALE LNP exhibits a base editing effect, cancer targeting, and remarkable therapy efficacy in NSCLC cancer-bearing mice. In conclusion, the targeted TALE LNP has the potential to treat lung cancer with KRAS gene mutation through an approach of transcription activator-like effector base editing.
