Joshua J Robinson, Di Zhang, Pratima Basak, Amogh Vaidya, Sumanta Chatterjee, Xiaoyan Bian, Minjeong Kim, Xizhen Lian, Yehui Sun, Erick Guerrero, Xu Wang, Sang M Lee, Shuai Liu, Junyu Gong, Mayank Tiwari, Godwin K Babanyinah, Mihaela C Stefan, Lukas Farbiak, Daniel J Siegwart
{"title":"降低脂质纳米颗粒的复杂性：三组分两性离子氨基脂靶向肝外mRNA递送。","authors":"Joshua J Robinson, Di Zhang, Pratima Basak, Amogh Vaidya, Sumanta Chatterjee, Xiaoyan Bian, Minjeong Kim, Xizhen Lian, Yehui Sun, Erick Guerrero, Xu Wang, Sang M Lee, Shuai Liu, Junyu Gong, Mayank Tiwari, Godwin K Babanyinah, Mihaela C Stefan, Lukas Farbiak, Daniel J Siegwart","doi":"10.1021/acsbiomaterials.5c00631","DOIUrl":null,"url":null,"abstract":"<p><p>Simplicity and chemical expansion of lipid nanoparticles (LNPs) offer the potential for increased therapeutic benefit of mRNA vaccines and medicines. 3-Component Zwitterionic Amino Lipid (ZAL) LNPs offer simplicity and varied organ target scope, though there is a lack of chemical and formulation exploration with this class of lipids. Herein, we report the synthesis and evaluation of ZALs with improved biocompatibility, enhanced mRNA delivery efficacy, and extrahepatic organ-specific delivery through derivation at the secondary hydroxyl position with opivalate, chloride, bromide, and acetate. Evaluation of these novel ZAL molecules revealed organ-specific delivery trends, changes in delivery efficacy, and an engineering framework for chemically modifying lipid components that correlate with each specific chemical modification. Furthermore, the most efficacious ZAL derivative, which contains an acetate modification, displayed enhanced immune cell transfection in an organ-specific manner. This study provides a roadmap for reducing the complexity of LNPs by decreasing the number of lipid components in an LNP from the canonical 4 lipids to 3 lipids and expands the chemical scope of LNPs capable of mediating extrahepatic delivery.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Reducing Complexity in Lipid Nanoparticles: Three-Component Zwitterionic Amino Lipids for Targeted Extrahepatic mRNA Delivery.\",\"authors\":\"Joshua J Robinson, Di Zhang, Pratima Basak, Amogh Vaidya, Sumanta Chatterjee, Xiaoyan Bian, Minjeong Kim, Xizhen Lian, Yehui Sun, Erick Guerrero, Xu Wang, Sang M Lee, Shuai Liu, Junyu Gong, Mayank Tiwari, Godwin K Babanyinah, Mihaela C Stefan, Lukas Farbiak, Daniel J Siegwart\",\"doi\":\"10.1021/acsbiomaterials.5c00631\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Simplicity and chemical expansion of lipid nanoparticles (LNPs) offer the potential for increased therapeutic benefit of mRNA vaccines and medicines. 3-Component Zwitterionic Amino Lipid (ZAL) LNPs offer simplicity and varied organ target scope, though there is a lack of chemical and formulation exploration with this class of lipids. Herein, we report the synthesis and evaluation of ZALs with improved biocompatibility, enhanced mRNA delivery efficacy, and extrahepatic organ-specific delivery through derivation at the secondary hydroxyl position with opivalate, chloride, bromide, and acetate. Evaluation of these novel ZAL molecules revealed organ-specific delivery trends, changes in delivery efficacy, and an engineering framework for chemically modifying lipid components that correlate with each specific chemical modification. Furthermore, the most efficacious ZAL derivative, which contains an acetate modification, displayed enhanced immune cell transfection in an organ-specific manner. This study provides a roadmap for reducing the complexity of LNPs by decreasing the number of lipid components in an LNP from the canonical 4 lipids to 3 lipids and expands the chemical scope of LNPs capable of mediating extrahepatic delivery.</p>\",\"PeriodicalId\":8,\"journal\":{\"name\":\"ACS Biomaterials Science & Engineering\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Biomaterials Science & Engineering\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1021/acsbiomaterials.5c00631\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, BIOMATERIALS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Biomaterials Science & Engineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1021/acsbiomaterials.5c00631","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
Reducing Complexity in Lipid Nanoparticles: Three-Component Zwitterionic Amino Lipids for Targeted Extrahepatic mRNA Delivery.
Simplicity and chemical expansion of lipid nanoparticles (LNPs) offer the potential for increased therapeutic benefit of mRNA vaccines and medicines. 3-Component Zwitterionic Amino Lipid (ZAL) LNPs offer simplicity and varied organ target scope, though there is a lack of chemical and formulation exploration with this class of lipids. Herein, we report the synthesis and evaluation of ZALs with improved biocompatibility, enhanced mRNA delivery efficacy, and extrahepatic organ-specific delivery through derivation at the secondary hydroxyl position with opivalate, chloride, bromide, and acetate. Evaluation of these novel ZAL molecules revealed organ-specific delivery trends, changes in delivery efficacy, and an engineering framework for chemically modifying lipid components that correlate with each specific chemical modification. Furthermore, the most efficacious ZAL derivative, which contains an acetate modification, displayed enhanced immune cell transfection in an organ-specific manner. This study provides a roadmap for reducing the complexity of LNPs by decreasing the number of lipid components in an LNP from the canonical 4 lipids to 3 lipids and expands the chemical scope of LNPs capable of mediating extrahepatic delivery.
期刊介绍：
ACS Biomaterials Science & Engineering is the leading journal in the field of biomaterials, serving as an international forum for publishing cutting-edge research and innovative ideas on a broad range of topics:
Applications and Health – implantable tissues and devices, prosthesis, health risks, toxicology
Bio-interactions and Bio-compatibility – material-biology interactions, chemical/morphological/structural communication, mechanobiology, signaling and biological responses, immuno-engineering, calcification, coatings, corrosion and degradation of biomaterials and devices, biophysical regulation of cell functions
Characterization, Synthesis, and Modification – new biomaterials, bioinspired and biomimetic approaches to biomaterials, exploiting structural hierarchy and architectural control, combinatorial strategies for biomaterials discovery, genetic biomaterials design, synthetic biology, new composite systems, bionics, polymer synthesis
Controlled Release and Delivery Systems – biomaterial-based drug and gene delivery, bio-responsive delivery of regulatory molecules, pharmaceutical engineering
Healthcare Advances – clinical translation, regulatory issues, patient safety, emerging trends
Imaging and Diagnostics – imaging agents and probes, theranostics, biosensors, monitoring
Manufacturing and Technology – 3D printing, inks, organ-on-a-chip, bioreactor/perfusion systems, microdevices, BioMEMS, optics and electronics interfaces with biomaterials, systems integration
Modeling and Informatics Tools – scaling methods to guide biomaterial design, predictive algorithms for structure-function, biomechanics, integrating bioinformatics with biomaterials discovery, metabolomics in the context of biomaterials
Tissue Engineering and Regenerative Medicine – basic and applied studies, cell therapies, scaffolds, vascularization, bioartificial organs, transplantation and functionality, cellular agriculture
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