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

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. A virus-mimicking polysaccharide-based multifunctional nanocomplex shows considerable endosomal escape activity for siRNA delivery, which is manifested via computational and biological tools. In vivo , the inherent targeting capability and feasible gene silencing potency of produced nanocomplex are confirmed in three independent inflammation murine models, suggesting the potential value of this versatile platform for inflammation-related diseases. Created with BioRender.com. [Display omitted] • On-demand designed, screen and synthesis of β-glucan-based nanoparticles for gene delivery. • Computational simulation to understand the mechanism of endosome escape capability from the developed nanosystem. • One-step production scheme without further surface chemical modification to achieve potent in vivo targeting. • Targeting efficiency and gene silencing capability were tested in three independent inflammatory murine models. • As a proof of concept, siTGF-β based nanoformulation showed potential therapeutic effect in murine cardiac fibrosis model. [ABSTRACT FROM AUTHOR]