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Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

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Chinese Chemical Letters 2024年第2期35卷 323-328页

作者： Qiu Wang Qikun Jiang Dan Li Zimeng Yang Lin Gao Fan Liu Chang Li Yao Feng Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Kangya of Ningxia Pharmaceutical Co.Ltd. Yinchuan 750000China

Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory ***,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative ***,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of ***,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver *** M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin ***,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of *** expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury *** a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

关键词： lipid nanoparticle Targeting siRNA delivery Acute liver injury Gene silencing Tumor necrosis factorα

A lipid nanoparticle platform incorporating trehalose glycolipid for exceptional mRNA vaccine safety

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Bioactive Materials 2024年第8期38卷 486-498页

作者： Seo-Hyeon Bae Soyeon Yoo Jisun Lee Hyo-Jung Park Sung Pil Kwon Harin Jin Sang-In Park Yu-Sun Lee Yoo-Jin Bang Gahyun Roh Seonghyun Lee Sue Bean Youn In Woo Kim Ho Rim Oh Ashraf K.El-Damasy Gyochang Keum Hojun Kim Hyewon Youn Jae-Hwan Nam Eun-Kyoung Bang Department of Medical and Biological Sciences The Catholic University of KoreaGyeonggi-doBucheonRepublic of Korea BK Four Department of Biotechnology The Catholic University of KoreaGyeonggi-doBucheonRepublic of Korea Center for Brain Technology Brain Science InstituteKorea Institute of Science and Technology(KIST)Seoul02792Republic of Korea Center for Advanced Biomolecular Recognition Korea Institute of Science and Technology(KIST)Seoul02792Republic of Korea Division of Bio-Medical Science and Technology KIST SchoolUniversity of Science and Technology(UST)SeoulRepublic of Korea SML Biopharm Gwangmyeong14353Republic of Korea KHU-KIST Department of Converging Science and Technology Graduate SchoolKyung Hee UniversitySeoul02447Republic of Korea Cancer Research Institute Seoul National University College of MedicineSeoul03080Republic of Korea Department of Nuclear Medicine Cancer Imaging CenterSeoul National University HospitalSeoul03080Republic of Korea

The rapid development of messenger RNA(mRNA)vaccines formulated with lipid nanoparticles(LNPs)has contributed to control of the COVID-19 ***,mRNA vaccines have raised concerns about their potential toxicity and clinical safety,including side effects,such as myocarditis,anaphylaxis,and *** this study,we investigated the potential of trehalose glycolipids-containing LNP(LNP S050L)to reduce the risks associated with ionizable *** glycolipids can form hydrogen bonds with polar biomolecules,allowing the formation of a stable LNP structure by replacing half of the ionizable *** efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity,***,mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity,including in the heart,spleen,and liver,while sustaining gene expression and immune efficiency,compared to conventional LNPs(Con-LNPs).Our findings suggest that LNP S050L,a trehalose glycolipid-based LNP,could facilitate the development of safe mRNA vaccines with improved clinical safety.

关键词： Trehalose glycolipid lipid nanoparticle mRNA vaccine Toxicity Immunogenicity

Efficient hepatic delivery and protein expression enabled by optimized mRNA and ionizable lipid nanoparticle

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Bioactive Materials 2020年第4期5卷 1053-1061页

作者： Tongren Yang Chunhui Li Xiaoxia Wang Deyao Zhao Mengjie Zhang Huiqing Cao Zicai Liang Haihua Xiao Xing-Jie Liang Yuhua Weng Yuanyu Huang School of Life Science Advanced Research Institute of Multidisciplinary ScienceInstitute of Engineering MedicineKey Laboratory of Molecular Medicine and BiotherapyBeijing Institute of TechnologyBeijing100081China Institute of Molecular Medicine Peking UniversityBeijing100871China Suzhou Ribo Life Science Co.Ltd. Jiangsu215300China Beijing National Laboratory for Molecular Science State Key Laboratory of Polymer Physical and ChemistryInstitute of ChemistryChinese Academy of ScienceBeijing100190China Chinese Academy of Sciences(CAS)Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing100190China School of Materials and the Environment Beijing Institute of TechnologyZhuhai519085China Department of Radiation Oncology The First Affiliated Hospital of Zhengzhou UniversityErqiZhengzhou450000China

mRNA is a novel class of therapeutic modality that holds great promise in vaccination,protein replacement therapy,cancer immunotherapy,immune cell engineering ***,optimization of mRNA molecules and efficient in vivo delivery are quite important but challenging for its broad *** we present an ionizable lipid nanoparticle(iLNP)based on iBL0713 lipid for in vitro and in vivo expression of desired proteins using codon-optimized *** encoding luciferase or erythropoietin(EPO)were prepared by in vitro transcription and formulated with proposed iLNP,to form iLP171/mRNA *** was revealed that both luciferase and EPO proteins were successfully expressed by human hepatocellular carcinoma cells and *** maximum amount of protein expression was found at 6 h *** expression efficiency of EPO with codon-optimized mRNA was significantly higher than that of unoptimized ***,no toxicity or immunogenicity was observed for these mRNA ***,our study provides a useful and promising platform for mRNA therapeutic development.

关键词： mRNA therapy lipid nanoparticle mRNA delivery Erythropoietin Codon optimization

lipid-nanoparticle-enabled nucleic acid therapeutics for liver disorders

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2885-2900页

作者： Porkizhi Arjunan Durga Kathirvelu Gokulnath Mahalingam Ashish Kumar Goel Uday George Zacharaiah Alok Srivastava Srujan Marepally Center for Stem Cell Research(A Unit of inStem Bengaluru)Christian Medical College CampusBagayamVellore 632002Tamil NaduIndia Manipal academy for higher education Mangalore 576104KarnatakaIndia Department of Hematology Christian Medical College&HospitalVellore 632004Tamil NaduIndia Department of Hepatology Christian Medical College&HospitalVellore 632004Tamil NaduIndia

Inherited genetic disorders of the liver pose a significant public health *** transplantation is often limited by the availability of donor livers and the exorbitant costs of immunosuppressive *** overcome these limitations,nucleic acid therapy provides a hopeful alternative that enables gene repair,gene supplementation,and gene silencing with suitable *** viral vectors are the most efficient and preferred for gene therapy,pre-existing immunity debilitating immune responses limit their *** a potential alternative,lipid nanoparticle-mediated vectors are being explored to deliver multiple nucleic acid forms,including pDNA,mRNA,siRNA,and ***,we discuss the broader applications of lipid nanoparticles,from protein replacement therapy to restoring the disease mechanism through nucleic acid delivery and gene editing,as well as multiple preclinical and clinical studies as a potential alternative to liver transplantation.

关键词： lipid nanoparticle Liver disorders Gene therapy Gene editing Nucleic acid delivery pDNA mRNA siRNA ASO Clinical trials

lipid nanoparticles deliver mRNA to the blood-brain barrier

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Nano Research 2024年第10期17卷 9126-9134页

作者： Yanina Kuzminich Avraham Shakked Randi Calkins Sebastian Rudden Camille Jones Jessie Doan Bora Jang Elisa Schrader Echeverri Ryan Zenhausern Liming Lian David Loughrey Hannah E.Peck Rachelle Wiese Dorothy Koveal Philip J.Santangelo James E.Dahlman George C.Woodruff School of Mechanical Engineering Georgia Institute of TechnologyAtlantaGA 30332USA Parker H.Petit Institute for Bioengineering and Biosciences Georgia Institute of TechnologyAtlantaGA 30332USA Wallace H.Coulter Department of Biomedical Engineering Emory University School of Medicine and Georgia Institute of TechnologyAtlantaGA 30332USA

lipid nanoparticles(LNPs)have delivered RNA to hepatocytes in patients after intravenous *** clinical data support efforts to design LNPs that transfect cells in the central nervous system(CNS).However,delivery to the CNS has been difficult,in large part because quantifying on-target delivery alongside common off-target cell types in adult mice remains *** we report methods to isolate different cell types from the CNS,and subsequently present mRNA delivery readouts using a liver-detargeted *** data suggest that LNPs without targeting ligands can transfect cerebral endothelial cells in mice after intravenous *** the difficulty of crossing the blood-brain barrier,they also underscore the value of quantifying delivery in the CNS with cell-type resolution instead of whole-tissue resolution.

关键词： lipid nanoparticle mRNA nanomedicine central nervous system blood-brain barrier

Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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National Science Review 2024年第6期11卷 285-293页

作者： Qiubing Chen Xuebin Wang Yizhou Zhang Ming Tian Junyi Duan Ying Zhang Hao Yin Departments of Urology and Laboratory Medicine Frontier Science Center for Immunology and Metabolism Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan University State Key Laboratory of Virology Tai Kang Center for Life and Medical Sciences Tai Kang Medical SchoolWuhan University Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan University Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical Sciences RNA Institute Wuhan University

lipid nanoparticles(LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

关键词： ionizable lipid lipid nanoparticle mRNA delivery base editor delivery Pcsk9

Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2950-2962页

作者： Wei Wang Shuo Feng Zhuyifan Ye Hanlu Gao Jinzhong Lin Defang Ouyang State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China

lipid nanoparticle(LNP) is commonly used to deliver mRNA ***,LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and *** study attempts to apply computational methods to accelerate the LNP development for mRNA ***,325 data samples of mRNA vaccine LNP formulations with IgG titer were *** machine learning algorithm,lightGBM,was used to build a prediction model with good performance(R^(2)>0.87).More importantly,the critical substructures of ionizable lipids in LNPs were identified by the algorithm,which well agreed with published *** animal experimental results showed that LNP using DLin-MC3-DMA(MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102,which was consistent with the model *** dynamic modeling further investigated the molecular mechanism of LNPs used in the *** result showed that the lipid molecules aggregated to form LNPs,and mRNA molecules twined around the *** summary,the machine learning predictive model for LNP-based mRNA vaccines was first developed,validated by experiments,and further integrated with molecular *** prediction model can be used for virtual screening of LNP formulations in the future.

关键词： lipid nanoparticle Ionizable lipid mRNA Vaccine Formulation prediction Machine learning LightGBM Molecular modeling

Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins,and drugs

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2624-2639页

作者： Yamin Li Zhongfeng Ye Hanyi Yang Qiaobing Xu Department of Biomedical Engineering Tufts UniversityMedfordMA 02155USA Department of Pharmacology State University of New YorkUpstate Medical UniversitySyracuseNY 13210USA

lipid nanoparticle(LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery *** can encapsulate and deliver a wide variety of bioactive agents,including the small molecule drugs,proteins and peptides,and nucleic ***,as the physicochemical properties of small-and macromolecular cargos can vary drastically,every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient *** group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug *** this Review,we highlight our recent progress in the design,synthesis,characterization,evaluation,and optimization of combinatorial LNPs with novel structures and properties for the delivery of small-and macromolecular therapeutics both in vitro and in *** delivery systems have enormous potentials for cancer therapy,antimicrobial applications,gene silencing,genome editing,and *** also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.

关键词： lipid nanoparticle Combinatorial library Drug delivery Cancer therapy Protein delivery Gene therapy

Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4591-4607页

作者： Wei Wang Shiwei Deng Jinzhong Lin Defang Ouyang aState Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Faculty of Health Sciences University of MacaoMacao 999078China State Key Laboratory of Genetic Engineering School of Life SciencesFudan UniversityShanghai 200438China Center for mRNA Translational Research Fudan UniversityShanghai 200438China Zhangjiang mRNA Innovation and Translation Center Fudan UniversityShanghai 200438China

The lipid nanoparticle(LNP)has been so far proven as a strongly effective delivery system for mRNA and ***,the mechanisms of LNP's distribution,metabolism,and elimination are complicated,while the transportation and pharmacokinetics(PK)of LNP are just sparsely investigated and simply *** study aimed to build a model for the transportation of RNA-LNP in Hela cells,rats,mice,and humans by physiologically based pharmacokinetic(PBPK)and quantum mechanics(QM)models with integrated multi-source *** with different ionizable lipids,particle sizes,and doses were modeled and compared by recognizing their critical parameters dominating *** interesting results were found by the *** example,the metabolism of ionizable lipids was first limited by the LNP disassembly rate instead of the hydrolyzation of ionizable lipids;the ability of RNA release from endosomes for three ionizable lipids was quantitively derived and can predict the probability of RNA ***,the biodegradability of three ionizable lipids was estimated by the QM method and the is generally consistent with the result of PBPK *** summary,the transportation model of RNA LNP among various species for the first time was successfully *** in vitro and in vivo pieces of evidence were integrated through QM/PBPK multi-level *** resulting new understandings are related to biodegradability,safety,and RNA release ability which are highly concerned issues of the *** would benefit the design and research of RNA-LNP in the future.

关键词： lipid nanoparticle RNA Ionizable lipid In vivo transportation Endosomal escape Metabolism Quantum mechanics Physiologically-based pharmacokinetics