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*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    5 Citations (Scopus)
    67 Downloads (Pure)

    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.
    Original languageEnglish
    Pages (from-to)120-132
    Number of pages13
    JournalJournal of Controlled Release
    Volume357
    Early online date29-Mar-2023
    DOIs
    Publication statusPublished - May-2023

    Keywords

    • β-Glucan
    • Endosomal escape
    • siRNA
    • Dectin-1
    • Myocardial infarction

    Fingerprint

    Dive into the research topics of 'Rational design of a polysaccharide-based viral mimicry nanocomplex for potent gene silencing in inflammatory tissues'. Together they form a unique fingerprint.

    Cite this