Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA
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 p...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/26/11/3238 |
| _version_ | 1797532333564231680 |
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| author | Shuang Liu Shaohui Deng Xiaoxia Li Du Cheng |
| author_facet | Shuang Liu Shaohui Deng Xiaoxia Li Du Cheng |
| author_sort | Shuang Liu |
| collection | DOAJ |
| description | 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(<span style="font-variant: small-caps;">l</span>-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. |
| first_indexed | 2024-03-10T10:57:40Z |
| format | Article |
| id | doaj.art-8cbce98a7e6544bf9889569dd12a5f4c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:57:40Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-8cbce98a7e6544bf9889569dd12a5f4c2023-11-21T21:43:58ZengMDPI AGMolecules1420-30492021-05-012611323810.3390/molecules26113238Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNAShuang Liu0Shaohui Deng1Xiaoxia Li2Du Cheng3PCFM 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, ChinaPCFM 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, ChinaPCFM 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, ChinaPCFM 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, ChinaThough 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(<span style="font-variant: small-caps;">l</span>-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.https://www.mdpi.com/1420-3049/26/11/3238small polyplexpH-sensitive PEG sheddingdisulfide bond-crosslinkingsiRNA deliverytargeting delivery |
| spellingShingle | Shuang Liu Shaohui Deng Xiaoxia Li Du Cheng Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA Molecules small polyplex pH-sensitive PEG shedding disulfide bond-crosslinking siRNA delivery targeting delivery |
| title | Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
| title_full | Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
| title_fullStr | Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
| title_full_unstemmed | Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
| title_short | Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA |
| title_sort | size and surface dual engineered small polyplexes for efficiently targeting delivery of sirna |
| topic | small polyplex pH-sensitive PEG shedding disulfide bond-crosslinking siRNA delivery targeting delivery |
| url | https://www.mdpi.com/1420-3049/26/11/3238 |
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