CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration
Abstract The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9‐mRN...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202300502 |
| _version_ | 1797786144844283904 |
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| author | Yunfei Zhao Yun Li Fan Wang Xuelan Gan Tianye Zheng Mengyue Chen Li Wei Jun Chen Chao Yu |
| author_facet | Yunfei Zhao Yun Li Fan Wang Xuelan Gan Tianye Zheng Mengyue Chen Li Wei Jun Chen Chao Yu |
| author_sort | Yunfei Zhao |
| collection | DOAJ |
| description | Abstract The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9‐mRNA/ single‐guide RNA (Cas9‐mRNA/sgRNA) in vitro and vivo, using carboxylesterase‐responsive cationic triadic copolymeric nanoparticles targeted proprotein convertase subtilisin/kexin type 9 (PCSK9) for hyperlipidemia amelioration is reported. A dimethyl biguanide derivative is designed and synthesized to form cationic block, and copolymerization onto prepolymer with propyl methacrylate, to fabricate a triadic copolymer mPEG‐b‐P(Met/n‐PMA). The copolymer can self‐assemble with Cas9‐mRNA/sgRNA, indicating the excellent potential of nanoparticles to form a delivery carrier. This vehicle can efficiently release RNA in response to the hepatocytes carboxylesterase for genome editing. It was demonstrated that the mPEG‐b‐P(Met/n‐PMA)/Cas9 mRNA/sgRNA nanoparticles effectively accumulated in hepatocytes, lead to the inhibition of PCSK9, and lowered the levels of Low‐density lipoprotein cholesterol and total cholesterol in mouse serum down 20% of nontreatment. Interestingly, the nanoparticles even enable multiple functions in the regulation of blood glucose and weight. This study establishes a novel method to achieve complex CRISPR components stable loading, safe delivery, and fixed‐point release, which expand the application of CRISPR delivery systems. |
| first_indexed | 2024-03-13T01:04:47Z |
| format | Article |
| id | doaj.art-4ad3dc3a7a6a4034ad6c496604065433 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-13T01:04:47Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-4ad3dc3a7a6a4034ad6c4966040654332023-07-06T07:39:03ZengWileyAdvanced Science2198-38442023-07-011019n/an/a10.1002/advs.202300502CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia AmeliorationYunfei Zhao0Yun Li1Fan Wang2Xuelan Gan3Tianye Zheng4Mengyue Chen5Li Wei6Jun Chen7Chao Yu8Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy Chongqing Medical University Chongqing 400016 P. R. ChinaAbstract The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9‐mRNA/ single‐guide RNA (Cas9‐mRNA/sgRNA) in vitro and vivo, using carboxylesterase‐responsive cationic triadic copolymeric nanoparticles targeted proprotein convertase subtilisin/kexin type 9 (PCSK9) for hyperlipidemia amelioration is reported. A dimethyl biguanide derivative is designed and synthesized to form cationic block, and copolymerization onto prepolymer with propyl methacrylate, to fabricate a triadic copolymer mPEG‐b‐P(Met/n‐PMA). The copolymer can self‐assemble with Cas9‐mRNA/sgRNA, indicating the excellent potential of nanoparticles to form a delivery carrier. This vehicle can efficiently release RNA in response to the hepatocytes carboxylesterase for genome editing. It was demonstrated that the mPEG‐b‐P(Met/n‐PMA)/Cas9 mRNA/sgRNA nanoparticles effectively accumulated in hepatocytes, lead to the inhibition of PCSK9, and lowered the levels of Low‐density lipoprotein cholesterol and total cholesterol in mouse serum down 20% of nontreatment. Interestingly, the nanoparticles even enable multiple functions in the regulation of blood glucose and weight. This study establishes a novel method to achieve complex CRISPR components stable loading, safe delivery, and fixed‐point release, which expand the application of CRISPR delivery systems.https://doi.org/10.1002/advs.202300502CES active destabilized strategyCRISPR/Cas9hyperlipidemia ameliorationliver fixed‐point releasemRNA deliveryPCSK9 |
| spellingShingle | Yunfei Zhao Yun Li Fan Wang Xuelan Gan Tianye Zheng Mengyue Chen Li Wei Jun Chen Chao Yu CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration Advanced Science CES active destabilized strategy CRISPR/Cas9 hyperlipidemia amelioration liver fixed‐point release mRNA delivery PCSK9 |
| title | CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration |
| title_full | CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration |
| title_fullStr | CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration |
| title_full_unstemmed | CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration |
| title_short | CES1‐Triggered Liver‐Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration |
| title_sort | ces1 triggered liver specific cargo release of crispr cas9 elements by cationic triadic copolymeric nanoparticles targeting gene editing of pcsk9 for hyperlipidemia amelioration |
| topic | CES active destabilized strategy CRISPR/Cas9 hyperlipidemia amelioration liver fixed‐point release mRNA delivery PCSK9 |
| url | https://doi.org/10.1002/advs.202300502 |
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