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 beta-glucans (EEPG) to endow the nano-complex 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 af-finity 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-beta 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.

Automated summary

Researchers developed a virus-mimicking polysaccharide nanocomplex for specific gene delivery to a subset of leukocytes. The nanocomplex exhibited pH-dependent endosomal membrane destabilization capabilities and efficient gene silencing potency against Dectin-1+ monocytes/macrophages. In murine inflammation models, the nanocomplex showed enhanced accumulation at cardiac lesion sites, indicating its exclusive targeting capability for ischemic heart diseases. This design has translational potential as a versatile platform in inflammation-related diseases.