Reverse Engineering of DNA and RNA Hybrid Origami Structures as Targeted Nanomedicine for KRAS-Mutated Lung Cancer Therapy

作者全名："Ding, Xiaotong; Chen, Chunfa; Liu, Qian; Yang, Yao; Wang, Guansong; Qian, Hang"

作者地址："[Ding, Xiaotong; Chen, Chunfa; Liu, Qian; Yang, Yao; Wang, Guansong; Qian, Hang] Third Mil Med Univ, Xinqiao Hosp, Inst Resp Dis, Chongqing 400037, Peoples R China; [Liu, Qian] Chongqing Med Univ, Lab Pharm & Chem, Lab Teaching & Management Ctr, Chongqing 400016, Peoples R China; [Liu, Qian] Chongqing Med Univ, Lab Teaching & Management Ctr, Lab Tissue & Cell Biol, Chongqing 400016, Peoples R China"

通信作者："Wang, GS; Qian, H (通讯作者)，Third Mil Med Univ, Xinqiao Hosp, Inst Resp Dis, Chongqing 400037, Peoples R China."

来源：ACS APPLIED POLYMER MATERIALS

ESI学科分类：　

WOS号：WOS:001027014900001

JCR分区：Q1

影响因子：4.4

年份：2023

卷号：5

期号：8

开始页：5880

结束页：5887

文献类型：Article

关键词：KRAS; hybrid origami; nanomedicine; aptamer; gene therapy

摘要："Nonsmall cell lung cancer (NSCLC), driven by KRAS gene mutations, is a highly malignant disease currently lacking targeted medicines, except for a specific G12C mutation. However, nanotechnology-based interventions and nanomedicines hold great promise as alternatives to traditional chemotherapy. In this study, we propose a reverse engineering strategy to design and assemble DNA and RNA hybrid origami nanostructures as nanomedicines for the therapy of KRAS-mutated NSCLC. Instead of using M13 DNA as a scaffold for origami design, whose scaffold sequence is constant, the proposed reverse engineering strategy uses a pool of staple sequences that are constant while the scaffold sequences are variable. We conducted a research study on concept verification by designing DNA and RNA hybrid origami nanotubular structures whose staple strands are antisense oligonucleotides (ASON) that are complementary to the full exon regions of KRAS mRNA. The scaffold RNA sequence is thus determined by the ASON sequences and the geometry of the origami design. Once inside the cancer cells, the structure degrades the RNA and releases ASON under the activation of RNase H to exert an antitumor effect. The results from cellular experiments and in vivo studies demonstrated that the hybrid origami structure, composed of DNA and RNA, effectively inhibited both cell proliferation and tumor progression. Remarkably, the proposed reverse engineering method is a universal strategy that can be extended to designing nanomedicines targeting other pathogenic genes and diseases and has good prospects."

基金机构："National Natural Science Foundation of China [32071379, 82070071]; Young PhD Incubation Program of Xinqiao Hospital, Army Military Medical [2022YQB024]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (32071379, 82070071) and the Young PhD Incubation Program of Xinqiao Hospital, Army Military Medical (2022YQB024)."