Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
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Authors: | Shuang Liu Shaohui Deng Xiaoxia Li Du Cheng |
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Institution: | 1.PCFM Lab of Ministry of Education & Guangzhou Key Laboratory of Flexible Electronic Materials and Wearable Devices, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China; (S.L.); (X.L.);2.Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China |
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Abstract: | Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes’ size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA. |
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Keywords: | small polyplex pH-sensitive PEG shedding disulfide bond-crosslinking siRNA delivery targeting delivery |
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