Lingling Shan,1 Yudie Li,1 Yifan Ma,2 Yang Yang,1 Jing Wang,1 Lei Peng,1 Weiwei Wang,1 Fang Zhao,1 Wanrong Li,1 Xiaoyuan Chen3– 6 

1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China; 2Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 3Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore; 4Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 5Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 6Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore

Correspondence: Xiaoyuan Chen; Lingling Shan, Email chen.shawn@nus.edu.sg; ntlinger-300@163.com

Background: While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.
Methods: We exploited nanoparticle coordination between ferric (Fe2+) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe2+-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula’s toxicity, imaging, and synergistic therapeutic effects.
Results: The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe2+-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.
Conclusion: Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy.

Keywords: DNA nanomaterials, targeting, imaging, synergistic therapy