Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Abstract

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.

Combating Cancer Stem-Like Cell-Derived Resistance to Anticancer Protein by Liposome-Mediated Acclimatization Strategy

“…The anionic pTRAIL/P was loaded into the cationic Sal/L to afford pTRAIL/Sal/L through electrostatic interaction, which had zeta potential of +32 mV and particle size of 101 nm (Figure b). Considering that cationic nanoparticles suffer from inferior stability and rapid clearance from the body and also cause hematotoxicity, we applied anionic HA to shield positive charge of pTRAIL/Sal/L. , c -HA was synthesized by grafting cholesterol moieties to the HA backbone (Figure S2). pTRAIL/Sal/L-HA was obtained by coating pTRAIL/Sal/L with c -HA via hydrophobic force between the lipid membrane of liposome and the cholesterol group of c -HA in addition to electrostatic interaction, as confirmed by charge conversion and size increase (Figure b).…”

“…Salinomycin (Sal), a polyether ionophore antibiotic, which has a superior effect on not only eliminating CSCs − but also upregulating the expression of DR4/5 on the CSCs, , is physically loaded in the lipid bilayer of liposome. To shield the cationic property of the pTRAIL and Sal coloaded liposome (pTRAIL/Sal/L) that leads to serum toxicity and rapid clearance, , cholesterol-grafted hyaluronic acid ( c -HA) is used to cloak pTRAIL/Sal/L through electrostatic and hydrophobic forces to acquire final formulation designated as pTRAIL/Sal/L-HA.…”

“…To shield the cationic property of the pTRAIL and Sal coloaded liposome (pTRAIL/Sal/L) that leads to serum toxicity and rapid clearance, 32,33 cholesterol-grafted hyaluronic acid (c-HA) is used to cloak pTRAIL/Sal/L through electrostatic and hydrophobic forces to acquire final formulation designated as pTRAIL/Sal/L-HA.…”

Homotypic Targeted Photosensitive Nanointerferer for Tumor Cell Cycle Arrest to Boost Tumor Photoimmunotherapy

“…These observations confirmed that the "proton sponge" effect of cationic protamine indeed facilitated the endo-/lysosomal escape of msiPCN. 34,42,43 Next, we used 2′,7′-dichlorofluorescein diacetate (DCFH-DA), a probe to detect ROS production in living cells, to assess whether the coating membranes affect the photodynamic effect of PCN. Compared with mPCN without irradiation, highintensity green fluorescence was observed in CT26 cells treated with mPCN under irradiation (660 nm, 30 mW cm −2 ) for 15 min (Figure S12), suggesting that PCN could also effectively carry out PDT in CT26 cells after coating cell membranes.…”

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

“…Gene delivery to the liver is a complex process, including transportation in blood circulation, accumulation in the liver, liver cells internalization through membrane fusion or endocytosis, and gene release in the cytosol or nucleus [141]. Gene delivery provides an exciting approach for the therapy of different diseases [142][143][144][145], as well as the antiinflammatory treatment of ALF. However, gene delivery has been hampered by the premature degradation, endosomal/lysosomal entrapment, undesired biodistribution, and minimal intracellular delivery [146].…”