Co-delivery of Cas9 mRNA and guide RNAs edits hepatitis B virus episomal and integration DNA in mouse and tree shrew models

Yi, Junzhu; Lei, Xinlin; Guo, Fangteng; Chen, Qiubing; Chen, Xueyong; Zhao, Kaitao; Zhu, Chengliang; Cheng, Xiaoming; Lin, Jiangwei; Yin, Hao; Xia, Yuchen

doi:10.1016/j.antiviral.2023.105618

Cited by 16 publications

(6 citation statements)

References 49 publications

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“…Ionizable lipid-based LNPs were formulated using a microfluidic mixing device, following a previously established protocol [ 38 ]. The formulation comprised ionizable lipid, helper lipid (DSPC), cholesterol, and a PEG-lipid conjugate (DMG-PEG2000) with a molar ratio of 50:10:38.5:1.5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The formulation comprised ionizable lipid, helper lipid (DSPC), cholesterol, and a PEG-lipid conjugate (DMG-PEG2000) with a molar ratio of 50:10:38.5:1.5 (Fig. 1B ) [ 38 ]. We used Firefly luciferase (Fluc) mRNA to measure the efficiency of in vitro and in vivo delivery [ 38 , 40 ].…”

Section: Resultsmentioning

confidence: 99%

“…1B ) [ 38 ]. We used Firefly luciferase (Fluc) mRNA to measure the efficiency of in vitro and in vivo delivery [ 38 , 40 ]. We examined various weight ratios of ionizable lipid to mRNA ranging from 2:1 to 20:1.…”

Section: Resultsmentioning

confidence: 99%

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

Chen,

Wang,

Zhang

et al. 2024

National Science Review

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Lipid nanoparticles 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 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Chen,

Wang,

Zhang

et al. 2024

National Science Review

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“…Additionally, the codelivery of immunomodulatory‐encoding mRNA with siRNA for checkpoint inhibitors was shown to counteract the immunosuppressive TME and achieve potent antitumor efficacy 115,116 . Advancements in LNP technology, which incorporate CRISPR complexes, have demonstrated their potential as adaptable formulation platforms for the delivery of chimeric antigen receptor (CAR), T cell receptor, and/or circular RNA into lymphocytes, thereby facilitating CAR‐T therapy 117‐126 . Furthermore, recent research has produced multiplexed dendrimer LNPs capable of codelivering siRNA, Cas9 mRNA, and sgRNA, indicating its potential for precise delivery and improved gene‐editing effectiveness 127‐129 …”

Section: Lipid‐based Nps As Drug Delivery System In Cancer Immunotherapymentioning

confidence: 99%

“…115,116 Advancements in LNP technology, which incorporate CRISPR complexes, have demonstrated their potential as adaptable formulation platforms for the delivery of chimeric antigen receptor (CAR), T cell receptor, and/or circular RNA into lymphocytes, thereby facilitating CAR-T therapy. [117][118][119][120][121][122][123][124][125][126] Furthermore, recent research has produced multiplexed dendrimer LNPs capable of codelivering siRNA, Cas9 mRNA, and sgRNA, indicating its potential for precise delivery and improved gene-editing effectiveness. [127][128][129] While LNPs represent a significant breakthrough for mRNA delivery into cells, it is crucial to consider the potential benefits of targeted delivery of mRNA-LNP vaccines to lymph nodes (LNs) in terms of improving immune responses and mitigating adverse effects such as hepatic damage.…”

Section: Delivery Of Therapeutic Nucleic Acids System By Cationic Lnpsmentioning

confidence: 99%

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Yang

Zhou

et al. 2023

MedComm

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Immune checkpoint inhibitors (ICIs) have shown remarkable success in cancer treatment. However, in cancer patients without sufficient antitumor immunity, numerous data indicate that blocking the negative signals elicited by immune checkpoints is ineffective. Drugs that stimulate immune activation‐related pathways are emerging as another route for improving immunotherapy. In addition, the development of nanotechnology presents a promising platform for tissue and cell type‐specific delivery and improved uptake of immunomodulatory agents, ultimately leading to enhanced cancer immunotherapy and reduced side effects. In this review, we summarize and discuss the latest developments in nanoparticles (NPs) for cancer immuno‐oncology therapy with a focus on lipid‐based NPs (lipid‐NPs), including the characteristics and advantages of various types. Using the agonists targeting stimulation of the interferon genes (STING) transmembrane protein as an exemplar, we review the potential of various lipid‐NPs to augment STING agonist therapy. Furthermore, we present recent findings and underlying mechanisms on how STING pathway activation fosters antitumor immunity and regulates the tumor microenvironment and provide a summary of the distinct STING agonists in preclinical studies and clinical trials. Ultimately, we conduct a critical assessment of the obstacles and future directions in the utilization of lipid‐NPs to enhance cancer immunotherapy.

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Advances in Nanocarriers for Delivering Therapeutic Agents Against Hepatitis B Virus

Li,

Yuan,

et al. 2024

Advanced NanoBiomed Research

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Hepatitis B virus (HBV) infection is a crucial public health issue and a major cause of liver disease, such as cirrhosis and hepatocellular carcinoma. At present, orally administered small molecule drugs, such as nucleoside / nucleotide analogues, are recommended as the first‐line treatment for HBV. However, the therapeutic efficacy of these drugs is hindered by off‐target toxicity caused by the whole‐body permeation distribution of these oral drugs. As an emerging drug delivery technology, systemically administered nanocarriers can enhance the aqueous solubility and stability of encapsulated drugs, prolong circulation times, and deliver them efficiently to the liver, showing great promise for increasing the safety and efficacy of small molecule drugs. Furthermore, nanocarriers also accelerate the clinical translation of new therapies, such as nucleic acids and vaccines. This review article highlights the progress of nanoparticle delivery systems in anti‐HBV therapeutics and discusses the opportunities and challenges for the future development of anti‐HBV nanotherapeutics.

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Co-delivery of Cas9 mRNA and guide RNAs edits hepatitis B virus episomal and integration DNA in mouse and tree shrew models

Cited by 16 publications

References 49 publications

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

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

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Advances in Nanocarriers for Delivering Therapeutic Agents Against Hepatitis B Virus

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