Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA
Ionizable lipids with branched tails have been used in lipid nanoparticles (LNPs)‐based messenger RNA (mRNA) therapeutics like COVID‐19 vaccines. However, due to the limited commercial availability of branched ingredients, a systematic analysis of how the branched tails affect LNP quality has been l...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley-VCH
2023-01-01
|
| Series: | Small Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/smsc.202200071 |
| _version_ | 1797956820928561152 |
|---|---|
| author | Kazuki Hashiba Yusuke Sato Masamitsu Taguchi Sachiko Sakamoto Ayaka Otsu Yoshiki Maeda Takuya Shishido Masao Murakawa Arimichi Okazaki Hideyoshi Harashima |
| author_facet | Kazuki Hashiba Yusuke Sato Masamitsu Taguchi Sachiko Sakamoto Ayaka Otsu Yoshiki Maeda Takuya Shishido Masao Murakawa Arimichi Okazaki Hideyoshi Harashima |
| author_sort | Kazuki Hashiba |
| collection | DOAJ |
| description | Ionizable lipids with branched tails have been used in lipid nanoparticles (LNPs)‐based messenger RNA (mRNA) therapeutics like COVID‐19 vaccines. However, due to the limited commercial availability of branched ingredients, a systematic analysis of how the branched tails affect LNP quality has been lacking to date. Herein, α‐branched tail lipids are focused, as they can be synthesized from simple commercially available chemicals, and the length of each chain can be independently controlled. Furthermore, symmetry and total carbon number can be used to describe α‐branched tails, facilitating the design of a systematic lipid library to elucidate “structure–property–function” relationships. Consequently, a lipid library is developed containing 32 different types of α‐branched tails. This library is used to demonstrate that branched chains increase LNP microviscosity and headgroup ionization ability in an acidic environment, which in turn enhances the stability and in vivo efficacy of mRNA‐LNPs. Of the branched lipids, CL4F 8‐6 LNPs carrying Cas9 mRNA and sgRNA could achieve 54% genome editing and 77% protein reduction with a single dose of 2.5 mg kg−1. This mechanism‐based data on branched lipids is expected to provide insights into rational lipid design and effective gene therapy in the future. |
| first_indexed | 2024-04-10T23:55:54Z |
| format | Article |
| id | doaj.art-a594fba2898d4a84917d111dc21355f3 |
| institution | Directory Open Access Journal |
| issn | 2688-4046 |
| language | English |
| last_indexed | 2024-04-10T23:55:54Z |
| publishDate | 2023-01-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | Small Science |
| spelling | doaj.art-a594fba2898d4a84917d111dc21355f32023-01-10T14:09:41ZengWiley-VCHSmall Science2688-40462023-01-0131n/an/a10.1002/smsc.202200071Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNAKazuki Hashiba0Yusuke Sato1Masamitsu Taguchi2Sachiko Sakamoto3Ayaka Otsu4Yoshiki Maeda5Takuya Shishido6Masao Murakawa7Arimichi Okazaki8Hideyoshi Harashima9Nucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanLaboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences Hokkaido University Kita-12, Nishi-6 Kita-Ku Sapporo 060-0812 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanNucleic Acid Medicine Business Division Nitto Denko Corporation 1-1-2, Shimohozumi Ibaraki Osaka 567-8680 JapanLaboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences Hokkaido University Kita-12, Nishi-6 Kita-Ku Sapporo 060-0812 JapanIonizable lipids with branched tails have been used in lipid nanoparticles (LNPs)‐based messenger RNA (mRNA) therapeutics like COVID‐19 vaccines. However, due to the limited commercial availability of branched ingredients, a systematic analysis of how the branched tails affect LNP quality has been lacking to date. Herein, α‐branched tail lipids are focused, as they can be synthesized from simple commercially available chemicals, and the length of each chain can be independently controlled. Furthermore, symmetry and total carbon number can be used to describe α‐branched tails, facilitating the design of a systematic lipid library to elucidate “structure–property–function” relationships. Consequently, a lipid library is developed containing 32 different types of α‐branched tails. This library is used to demonstrate that branched chains increase LNP microviscosity and headgroup ionization ability in an acidic environment, which in turn enhances the stability and in vivo efficacy of mRNA‐LNPs. Of the branched lipids, CL4F 8‐6 LNPs carrying Cas9 mRNA and sgRNA could achieve 54% genome editing and 77% protein reduction with a single dose of 2.5 mg kg−1. This mechanism‐based data on branched lipids is expected to provide insights into rational lipid design and effective gene therapy in the future.https://doi.org/10.1002/smsc.202200071branched tailgenome editingionizable lipidslipid nanoparticlesmRNA |
| spellingShingle | Kazuki Hashiba Yusuke Sato Masamitsu Taguchi Sachiko Sakamoto Ayaka Otsu Yoshiki Maeda Takuya Shishido Masao Murakawa Arimichi Okazaki Hideyoshi Harashima Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA Small Science branched tail genome editing ionizable lipids lipid nanoparticles mRNA |
| title | Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA |
| title_full | Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA |
| title_fullStr | Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA |
| title_full_unstemmed | Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA |
| title_short | Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA |
| title_sort | branching ionizable lipids can enhance the stability fusogenicity and functional delivery of mrna |
| topic | branched tail genome editing ionizable lipids lipid nanoparticles mRNA |
| url | https://doi.org/10.1002/smsc.202200071 |
| work_keys_str_mv | AT kazukihashiba branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT yusukesato branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT masamitsutaguchi branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT sachikosakamoto branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT ayakaotsu branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT yoshikimaeda branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT takuyashishido branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT masaomurakawa branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT arimichiokazaki branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna AT hideyoshiharashima branchingionizablelipidscanenhancethestabilityfusogenicityandfunctionaldeliveryofmrna |