Rational design of a polysaccharide-based viral mimicry nanocomplex for potent gene silencing in inflammatory tissues

Han Gao; Shiqi Wang; Qiang Long; Ruoyu Cheng; Wenhua Lian; Artturi Koivuniemi; Ming Ma; Baoding Zhang; Jouni Hirvonen; Xianming Deng; Zehua Liu; Xiaofeng Ye; Hélder A Santos

doi:10.1016/j.jconrel.2023.03.037

Rational design of a polysaccharide-based viral mimicry nanocomplex for potent gene silencing in inflammatory tissues

J Control Release. 2023 May:357:120-132. doi: 10.1016/j.jconrel.2023.03.037. Epub 2023 Mar 29.

Authors

Han Gao¹, Shiqi Wang², Qiang Long³, Ruoyu Cheng¹, Wenhua Lian⁴, Artturi Koivuniemi², Ming Ma⁵, Baoding Zhang⁴, Jouni Hirvonen², Xianming Deng⁴, Zehua Liu⁶, Xiaofeng Ye⁷, Hélder A Santos⁸

Affiliations

¹ Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, Groningen 9713 AV, the Netherlands; W.J. Kolff Institute for Biomedical Engineering and Materials Science, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, Groningen 9713 AV, the Netherlands; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
² Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
³ Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁵ Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
⁶ Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland. Electronic address: zehua.liu@helsinki.fi.
⁷ Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China. Electronic address: yxf11612@rjh.com.cn.
⁸ Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, Groningen 9713 AV, the Netherlands; W.J. Kolff Institute for Biomedical Engineering and Materials Science, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, Groningen 9713 AV, the Netherlands; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland. Electronic address: h.a.santos@umcg.nl.

PMID: 36963635
DOI: 10.1016/j.jconrel.2023.03.037

Abstract

Rational design and fabrication of small interfering RNA (siRNA) delivery system with simple production scheme, specific targeting capability, responsiveness to endogenous stimuli and potential multi-functionalities remains technically challenging. Herein, we screen and design a virus-mimicking polysaccharide nanocomplex that shows specific gene delivery capability in a selective subset of leukocytes. A virus-inspired poly (alkyl methacrylate-co-methacrylic acid) fragment was conjugated on barley β-glucans (EEPG) to endow the nanocomplex with pH-dependent endosomal membrane destabilization capabilities, as confirmed both biologically and computationally. siRNA loaded EEPG nanocomplex is feasibly fabricated in a single-step manner, which exhibit efficient gene silencing efficacy towards Dectin-1⁺ monocytes/macrophages. The inherent targeting affinity and feasible gene silencing potency of EEPG nanocomplex are investigated in three independent murine inflammation models, including myocardial infarction, lung fibrosis and acute liver damage. Significant enhanced accumulation level of EEPG nanocomplex is observed in cardiac lesion site, indicating its exclusive targeting capability for ischemic heart diseases. As a proof of concept, siTGF-β based gene therapy is confirmed in murine model with heart fibrosis. Overall, our findings suggest the designed EEPG nanocomplex is favorable for siRNA delivery, which might have translational potential as a versatile platform in inflammation-related diseases.

Keywords: Dectin-1; Endosomal escape; Myocardial infarction; siRNA; β-Glucan.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endosomes
Gene Silencing*
Gene Transfer Techniques*
Genetic Therapy
Mice
RNA, Small Interfering / genetics

Substances

RNA, Small Interfering