Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

被引：136

作者：

Zhang, Xinfu ^{[1
,2
]}

Zhao, Weiyu ^{[1
]}

Nguyen, Giang N. ^{[3
]}

Zhang, Chengxiang ^{[1
]}

Zeng, Chunxi ^{[1
]}

Yan, Jingyue ^{[1
]}

Du, Shi ^{[1
]}

Hou, Xucheng ^{[1
]}

Li, Wenqing ^{[1
]}

Jiang, Justin ^{[1
]}

Deng, Binbin ^{[4
]}

McComb, David W. ^{[4
,5
]}

Dorkin, Robert ^{[6
]}

Shah, Aalok ^{[6
]}

Barrera, Luis ^{[6
]}

Gregoire, Francine ^{[6
]}

Singh, Manmohan ^{[6
]}

Chen, Delai ^{[6
]}

Sabatino, Denise E. ^{[3
,7
]}

Dong, Yizhou ^{[1
,8
,9
,10
,11
,12
]}

机构：

[1] Ohio State Univ, Coll Pharm, Div Pharmaceut & Pharmacol, Columbus, OH 43210 USA

[2] Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116024, Peoples R China

[3] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[4] Ohio State Univ, Ctr Electron Microscopy & Anal, Dept Mat Sci & Engn, Columbus, OH 43210 USA

[5] Ohio State Univ, Dept Mat Sci & Engn, Columbus, OH 43210 USA

[6] Beam Therapeut, Cambridge, MA 02139 USA

[7] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA

[9] Ohio State Univ, Ctr Clin & Translat Sci, Columbus, OH 43210 USA

[10] Ohio State Univ, Comprehensive Canc Ctr, Columbus, OH 43210 USA

[11] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA

[12] Ohio State Univ, Dept Radiat Oncol, Columbus, OH 43210 USA

来源：

SCIENCE ADVANCES | 2020年 / 6卷 / 34期

关键词：

FACTOR-VIII; OPTIMIZATION; THERAPY; SYSTEM; DNA;

D O I：

10.1126/sciadv.abc2315

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications. Here, we constructed a series of lipid-like nanomaterials (LLNs), named functionalized TT derivatives (FTT), for mRNA-based therapeutic applications in vivo. After screenings on the materials, we identified FTT5 as a lead material for efficient delivery of long mRNAs, such as human factor VIII (hFVIII) mRNA (similar to 4.5 kb) for expression of hFVIII protein in hemophilia A mice. Moreover, FTT5 LLNs demonstrated high percentage of base editing on PCSK9 in vivo at a low dose of base editor mRNA (similar to 5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.

引用

页数：8

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