Antiangiogenic Therapeutic mRNA Delivery Using Lung-Selective Polymeric Nanomedicine for Lung Cancer Treatment

作者：Ngoc Duy Le, Bảo Lộc Nguyễn, Basavaraj R. Patil, HeeSang Chun, Siyoon Kim, Thi Oanh Oanh Nguyen, Sunil Mishra, Sudarshan Tandukar, Jae‐Hoon Chang, Dong Young Kim, Sung Giu Jin, Han‐Gon Choi, Sae‐Kwang Ku, Jeonghwan Kim, Jong Oh Kim · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.3c13039 · 被引用次数：53 · 研究领域：RNA Interference and Gene Delivery、Nanoparticle-Based Drug Delivery、Advanced biosensing and bioanalysis techniques

Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and i...