Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues DOI Creative Commons
Yulia Eygeris, Mohit Gupta, Jeonghwan Kim

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(11)

Published: March 4, 2024

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report identification and evaluation containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized Gewald reaction, allowing for modular lipid design with functional constituents at various positions ring. Through rational structure, prepared 47 identified some structural criteria required in efficient mRNA (messenger RNA) encapsulation vitro vivo. Notably, none tested have pH-response profile like traditional lipids, potentially due electron delocalization core. Placement tails localization headgroup core endow capability reach tissues. Using high-throughput formulation barcoding techniques, optimized formulations select two top lipids— 20b 29d —and investigated their biodistribution mice. enabled LNPs transfect liver spleen, LNP transfected lung spleen. Unexpectedly, was especially potent retina no acute toxicity, leading photoreceptors retinal pigment epithelium non-human primates.

Language: Английский

The role of lipid components in lipid nanoparticles for vaccines and gene therapy DOI

Camilla Hald Albertsen,

Jayesh A. Kulkarni, Dominik Witzigmann

et al.

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 188, P. 114416 - 114416

Published: July 3, 2022

Language: Английский

Citations

626
Chemistry of Lipid Nanoparticles for RNA Delivery DOI
Yulia Eygeris, Mohit Gupta, Jeonghwan Kim

et al.

Accounts of Chemical Research, Journal Year: 2021, Volume and Issue: 55(1), P. 2 - 12

Published: Dec. 1, 2021

ConspectusLipid nanoparticles (LNPs) are a type of lipid vesicles that possess homogeneous core. These widely used in small-molecule drug and nucleic acid delivery recently gained much attention because their remarkable success as platform for COVID-19 mRNA vaccines. Nonetheless, the utility transient protein expression induced by extends far beyond vaccines against infectious diseases─they also hold promise cancer vaccines, replacement therapies, gene editing components rare genetic diseases. However, naked is inherently unstable prone to rapid degradation nucleases self-hydrolysis. Encapsulation within LNPs protects from extracellular ribonucleases assists with intracellular delivery.In this Account, we discuss core features RNA delivery. We focus our on designed deliver mRNA; however, include examples siRNA-LNP where appropriate highlight commonalities dissimilarities due structure. First, introduce concept LNPs, advantages disadvantages utilizing acids therapeutic agents, general reasoning behind molecular makeup LNPs. briefly most recent clinical successes LNP-based therapies. Second, describe theory methods LNP self-assembly. The common idea all preparation inducing electrostatic interactions between charged lipids promoting nanoparticle growth via hydrophobic interactions. Third, break down composition special fundamental properties purposes each component. This includes identified design criteria, commercial sourcing, impact trafficking, contribution One key ionizable lipids, which initiate binding endosomal membranes facilitate cytosolic release; roles other should not be disregarded, they associated stability, clearance, distribution Fourth, review attributes constructs whole can heavily influence size, charge, internal structure, packing, membrane hydration, affinity toward biomacromolecules. specific techniques examine these how adjusted. Finally, offer perspective future therapies some questions remain realm formulation optimization.

Language: Английский

Citations

513
Self-assembled mRNA vaccines DOI Open Access
Jeonghwan Kim, Yulia Eygeris, Mohit Gupta

et al.

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 170, P. 83 - 112

Published: Jan. 2, 2021

Language: Английский

Citations

390
Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles DOI Creative Commons
Federica Sebastiani, Marianna Yanez Arteta,

Michael Lerche

et al.

ACS Nano, Journal Year: 2021, Volume and Issue: 15(4), P. 6709 - 6722

Published: March 23, 2021

Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there still challenges to use this formulation delivery. LNPs typically a mixture cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and PEG-lipid. The structural characterization mRNA-containing (mRNA-LNPs) is crucial full understanding way which they function, but information alone not enough predict their fate upon entering bloodstream. biodistribution cellular uptake affected surface composition as well extracellular present at site LNP administration,

Language: Английский

Citations

259
Innate immune mechanisms of mRNA vaccines DOI Creative Commons
Rein Verbeke, Michael J. Hogan, Karin Loré

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(11), P. 1993 - 2005

Published: Nov. 1, 2022

Language: Английский

Citations

250
Lipid-Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Components DOI Creative Commons
Pardis Kazemian,

Si-Yue Yu,

Sarah B. Thomson

et al.

Molecular Pharmaceutics, Journal Year: 2022, Volume and Issue: 19(6), P. 1669 - 1686

Published: May 20, 2022

Gene editing mediated by CRISPR/Cas9 systems is due to become a beneficial therapeutic option for treating genetic diseases and some cancers. However, there are challenges in delivering CRISPR components which necessitate sophisticated delivery safe effective genome editing. Lipid nanoparticles (LNPs) have an attractive nonviral platform CRISPR-mediated their low immunogenicity application flexibility. In this review, we provide background of gene therapy, as well LNPs applicable characteristics components. We then highlight the delivery, driven significant development new, safe, optimized LNP formulations past decade. Finally, discuss considerations using deliver future perspectives on clinical translation LNP-CRISPR

Language: Английский

Citations

157
Functional siRNA Delivery by Extracellular Vesicle–Liposome Hybrid Nanoparticles DOI Creative Commons
Martijn J.W. Evers, Simonides Immanuel van de Wakker,

Ellis M. de Groot

et al.

Advanced Healthcare Materials, Journal Year: 2021, Volume and Issue: 11(5)

Published: Aug. 11, 2021

The therapeutic use of RNA interference is limited by the inability siRNA molecules to reach their site action, cytosol target cells. Lipid nanoparticles, including liposomes, are commonly employed as carrier systems overcome this hurdle, although widespread remains due a lack delivery efficiency. More recently, nature's own carriers RNA, extracellular vesicles (EVs), increasingly being considered alternative vehicles intrinsic properties. However, they difficult load with exogenous cargo. Here, EV-liposome hybrid nanoparticles (hybrids) prepared and evaluated an system combining properties both liposomes EVs. It shown that hybrids spherical particles encapsulating siRNA, contain EV-surface makers, functionally deliver different cell types. functional behavior hybrids, in terms cellular uptake, toxicity, gene-silencing efficacy, altered compared varies among recipient Moreover, produced cardiac progenitor (CPC) derived-EVs retain attributed CPC-EVs such activation endothelial signaling migration. To conclude, combine benefits synthetic biological drug might serve future siRNA.

Language: Английский

Citations

150
Targeting cancer with mRNA–lipid nanoparticles: key considerations and future prospects DOI Open Access
Edo Kon, Nitay Ad‐El, Inbal Hazan‐Halevy

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(11), P. 739 - 754

Published: Aug. 16, 2023

Language: Английский

Citations

146
Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics DOI Creative Commons
Yeji Lee, Michaela Jeong, Jeongeun Park

et al.

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(10), P. 2085 - 2096

Published: Oct. 2, 2023

Abstract Several studies have utilized a lipid nanoparticle delivery system to enhance the effectiveness of mRNA therapeutics and vaccines. However, these nanoparticles are recognized as foreign materials by body stimulate innate immunity, which in turn impacts adaptive immunity. Therefore, it is crucial understand specific type immune response triggered nanoparticles. This article provides an overview immunological body, explores how activate system, examines adverse effects immunogenicity-related development pathways associated with Finally, we highlight explore strategies for regulating immunogenicity

Language: Английский

Citations

143
Nanotechnology for modern medicine: next step towards clinical translation DOI Open Access
Shrey Sindhwani, Warren C. W. Chan

Journal of Internal Medicine, Journal Year: 2021, Volume and Issue: 290(3), P. 486 - 498

Published: Jan. 22, 2021

Abstract The field of nanotechnology has been a significant research focus in the last thirty years. This emphasis is due to unique optical, electrical, magnetic, chemical and biological properties materials approximately ten thousand times smaller than diameter hair strand. Researchers have developed methods synthesize characterize large libraries nanomaterials demonstrated their preclinical utility. We entered new phase nanomedicine development, where translate these technologies benefit patients. review article provides an overview nanomedicine's properties, current state field, discusses challenge clinical translation. Finally, we discuss need build strengthen partnerships between engineers clinicians create feedback loop bench bedside. partnership will guide fundamental studies on nanoparticle–biological interactions, address challenges change development evaluation drug delivery systems, sensors, imaging agents therapeutic systems.

Language: Английский

Citations

139