Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes.Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion...Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes.Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators,therefore causing or aggravating insulin resistance.Herein,we develop collaborative assemblies using a“one-pot”synthesis method for macrophage-specific delivery of small interfering RNAs(siRNAs)that target the inflammatory proteins.Ternary nanocomplex(NC)composed of the siRNA molecule,a synthetic thiol-bearing methacrylated hyaluronic acid(sm-HA)and protamine forms through an electrostatic-driven physical assembly,which is chemically crosslinked to acquire the collaboratively assembled nanocapsule(cNC)concurrently.The obtained cNC displays significantly higher stability than NC.Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation,active targeting,or controlled siRNA release.cNC-F decorated with folic acid,a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model.cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins(>40%reduction)and ameliorating the insulin resistance symptoms of the obese mice.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81673381,81971730,and 81773957)the National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(No.2019ZX09201001-001-001)+2 种基金the Project of State Key Laboratory of Natural Medicines of China Pharmaceutical University(Nos.SKLNMZZCX201820 and SKLNMZZ202024)the“Double First-Class”Project of CPU(Nos.CPU2018GF05 and CPU2018GF04)the 111 Project(No.B16046).
文摘Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes.Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators,therefore causing or aggravating insulin resistance.Herein,we develop collaborative assemblies using a“one-pot”synthesis method for macrophage-specific delivery of small interfering RNAs(siRNAs)that target the inflammatory proteins.Ternary nanocomplex(NC)composed of the siRNA molecule,a synthetic thiol-bearing methacrylated hyaluronic acid(sm-HA)and protamine forms through an electrostatic-driven physical assembly,which is chemically crosslinked to acquire the collaboratively assembled nanocapsule(cNC)concurrently.The obtained cNC displays significantly higher stability than NC.Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation,active targeting,or controlled siRNA release.cNC-F decorated with folic acid,a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model.cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins(>40%reduction)and ameliorating the insulin resistance symptoms of the obese mice.
