Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance
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CT 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.
KEYWORDS small interfering RNA (siRNA) delivery, collaborative assembly, nanomedicine, insulin resistance, diabetes
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Introduction
RNA interference (RNAi) has emerged as a potent therapeutic strategy against a vast array of human diseases [1, 2]. The RNAi therapeutics, such as small interfering RNAs (siRNAs) or microRNAs, work by degrading messenger RNAs (mRNAs), blocking gene expression, and therefore silencing the diseaserelevant proteins [3, 4], which have significant advantages of high specificity and efficiency over conventional chemotherapeutics. Recently, two siRNA drugs, Onpattro (patisiran) and Givlaari (givosiran) were approved for the treatment of peripheral nerve disease (polyneuropathy) and acute hepatic porpyria, respectively [5]. However, a number of daunting challenges still remain [6, 7]. For example, siRNAs are unstable and vulnerable to serum nuclease, and it is difficult for them to penetrate lipid membrane due to their large molecular weight and high hydrophilicity. Many viral and non-viral carriers have been developed to enhance the siRNA delivery efficiency. The viral vectors possess high transduction efficiency, such as adenoviruses, lentiviruses, and retroviruses, but are subject to severe immunotoxicity [8, 9]. The non-viral carriers based upon cationic lipids or polymers are often applied to pack anionic siRNA to form a binary complex through electrostatic interaction [10–12], which supports enhanced nuclease resistance, cellular uptake, and intracellular transportation [13, 14]. However, highly positive
surface charge of the assembled complex may cause serum toxicities by activating complement s
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