Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo

Nature Biotechnology, Journal Year: 2024, Volume and Issue: 42(10), P. 1526 - 1537

Published: Jan. 8, 2024

Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient vitro vivo delivery prime components, however, remains a challenge. Here we report editor engineered virus-like particles (PE-eVLPs) that deliver proteins, guide RNAs nicking single as transient ribonucleoprotein complexes. We systematically v3 v3b PE-eVLPs with 65- to 170-fold higher efficiency human cells compared PE-eVLP construct based on our previously reported base eVLP architecture. In two mouse models genetic blindness, injections resulted therapeutically relevant levels the retina, protein expression restoration partial visual function rescue. Optimized support ribonucleoproteins, enhancing potential safety by reducing off-target obviating possibility oncogenic transgene integration.

Language: Английский

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mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: Oct. 7, 2023

mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating immune system. With regard mRNA vaccines, researchers modified structure enhance its stability promote systemic tolerance of antigenic presentation non-inflammatory contexts. Still, delivery naked mRNAs is inefficient results low levels antigen protein production. As such, lipid nanoparticles been utilized improve protect cargo from extracellular degradation. This advance was milestone development vaccines dispelled skepticism about technology yield clinically approved medicines. Following resounding success COVID-19, many other proposed treatment variety diseases. review begins discussion modifications vehicles, well factors that influence administration routes. Then, we summarize applications discuss further key points pertaining preclinical targeting wide range Finally, latest market trends future drugs.

Language: Английский

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The 60-year evolution of lipid nanoparticles for nucleic acid delivery

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 709 - 722

Published: July 4, 2024

Language: Английский

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mRNA-based therapeutics: looking beyond COVID-19 vaccines

The Lancet, Journal Year: 2024, Volume and Issue: 403(10432), P. 1192 - 1204

Published: March 1, 2024

Language: Английский

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Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery

Advanced Materials, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 4, 2023

Abstract Lipid‐based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, NAD delivery efficiency and safety still unsatisfactory, which are, to a large extent, due existence of multi‐level physiological barriers in vivo. It is important elucidate interactions between these LBNPs, will guide more rational design efficient with low adverse effects facilitate broader therapeutics. This review describes obstacles challenges biological at systemic, organ, sub‐organ, cellular, subcellular levels. The strategies overcome comprehensively reviewed, mainly including physically/chemically engineering LBNPs directly modifying by auxiliary treatments. Then potentials successful translation preclinical studies into clinic discussed. In end, forward look on manipulating protein corona (PC) addressed, may pull off trick overcoming those significantly improve efficacy LBNP‐based NADs

Language: Английский

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Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 5, 2024

Abstract Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in material structures compositions systematically the pulmonary hepatic (respectively) distribution expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation LNP compositions. Contrary current paradigms, our findings demonstrate that cholesterol phospholipid dispensable for functionality. Specifically, cholesterol-removal addresses persistent challenge preventing nanoparticle tissues. By modulating simplifying intrinsic components, concurrent translation achieved lung liver, respectively. This targeting strategy applicable existing with potential expand progress precise therapy diverse diseases.

Language: Английский

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Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Nature Nanotechnology, Journal Year: 2024, Volume and Issue: 19(9), P. 1409 - 1417

Published: May 23, 2024

Language: Английский

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Frameworks for transformational breakthroughs in RNA-based medicines

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(6), P. 421 - 444

Published: May 13, 2024

Language: Английский

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IL7 increases targeted lipid nanoparticle–mediated mRNA expression in T cells in vitro and in vivo by enhancing T cell protein translation

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(13)

Published: March 21, 2024

The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) allow for efficient delivery payloads T cells express protein. As percentage protein expressing induced by intravenous injection CD5/tLNP is relatively low (4-20%), our goal was find ways increase mRNA-induced translation efficiency. We showed that cell activation using anti-CD3 antibody improved expression after transfection vitro but not vivo. health increased cytokines, therefore, mCherry as a reporter, we found culturing either mouse or human cytokine IL7 significantly delivered both CD4 + CD8 vitro. By pre-treating mice systemic followed tLNP administration, observed Transcriptomic analysis treated revealed enhanced genomic pathways associated translation. Improved translational ability demonstrated showing levels electroporation cultured presence IL7, IL2 IL15. These data show selectively increases cells, this property improve tLNP-delivered

Language: Английский

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Lipid nanoparticle-based strategies for extrahepatic delivery of nucleic acid therapies – challenges and opportunities

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 370, P. 763 - 772

Published: May 17, 2024

Language: Английский

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