Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation DOI
Jeonghwan Kim, Antony Jozić, Yuxin Lin

et al.

ACS Nano, Journal Year: 2022, Volume and Issue: 16(9), P. 14792 - 14806

Published: Aug. 29, 2022

Despite lipid nanoparticles' (LNPs) success in the effective and safe delivery of mRNA vaccines, an inhalation-based therapy for lung diseases remains challenging. LNPs tend to disintegrate due shear stress during aerosolization, leading ineffective delivery. Therefore, need remain stable through process nebulization mucus penetration, yet labile enough endosomal escape. To meet these opposing needs, we utilized PEG enhance surficial stability with inclusion a cholesterol analog, β-sitosterol, improve Increased concentrations enhanced resistance while β-sitosterol provided polyhedral shape, facilitating The optimized exhibited uniform particle distribution, morphology, rapid mucosal diffusion gene transfection. Inhaled led localized protein production mouse without pulmonary or systemic toxicity. Repeated administration sustained lungs. Lastly, encoding cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after CFTR-deficient animal model, resulting expression this therapeutic protein. This study demonstrated rational design approach clinical translation inhalable LNP-based therapies.

Language: Английский

Lipid nanoparticles for mRNA delivery DOI Open Access
Xucheng Hou,

Tal Zaks,

Róbert Langer

et al.

Nature Reviews Materials, Journal Year: 2021, Volume and Issue: 6(12), P. 1078 - 1094

Published: Aug. 10, 2021

Language: Английский

Citations

2234
mRNA vaccines for infectious diseases: principles, delivery and clinical translation DOI Open Access
Namit Chaudhary, Drew Weissman, Kathryn A. Whitehead

et al.

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(11), P. 817 - 838

Published: Aug. 25, 2021

Language: Английский

Citations

992
Drug delivery systems for RNA therapeutics DOI Open Access
Kalina Paunovska, David Loughrey, James E. Dahlman

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(5), P. 265 - 280

Published: Jan. 4, 2022

Language: Английский

Citations

820
Engineered biomaterials for in situ tissue regeneration DOI
Akhilesh K. Gaharwar, Irtisha Singh, Ali Khademhosseini

et al.

Nature Reviews Materials, Journal Year: 2020, Volume and Issue: 5(9), P. 686 - 705

Published: July 6, 2020

Language: Английский

Citations

637
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

487
Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing DOI
Shuai Liu, Qiang Cheng, Tuo Wei

et al.

Nature Materials, Journal Year: 2021, Volume and Issue: 20(5), P. 701 - 710

Published: Feb. 4, 2021

Language: Английский

Citations

445
Lipid nanoparticles for nucleic acid delivery: Current perspectives DOI
Eleni Samaridou, James Heyes, Peter Lutwyche

et al.

Advanced Drug Delivery Reviews, Journal Year: 2020, Volume and Issue: 154-155, P. 37 - 63

Published: Jan. 1, 2020

Language: Английский

Citations

440
mRNA-based therapeutics: powerful and versatile tools to combat diseases DOI Creative Commons
Shugang Qin,

Xiaoshan Tang,

Yu‐Ting Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: May 21, 2022

Abstract The therapeutic use of messenger RNA (mRNA) has fueled great hope to combat a wide range incurable diseases. Recent rapid advances in biotechnology and molecular medicine have enabled the production almost any functional protein/peptide human body by introducing mRNA as vaccine or agent. This represents rising precision field with promise for preventing treating many intractable genetic In addition, vitro transcribed achieved programmed production, which is more effective, faster design well flexible cost-effective than conventional approaches that may offer. Based on these extraordinary advantages, vaccines characteristics swiftest response large-scale outbreaks infectious diseases, such currently devastating pandemic COVID-19. It always been scientists’ desire improve stability, immunogenicity, translation efficiency, delivery system achieve efficient safe mRNA. Excitingly, scientific dreams gradually realized rapid, amazing achievements biology, technology, vaccinology, nanotechnology. this review, we comprehensively describe mRNA-based therapeutics, including their principles, manufacture, application, effects, shortcomings. We also highlight importance optimization systems successful therapeutics discuss key challenges opportunities developing tools into powerful versatile genetic, infectious, cancer, other refractory

Language: Английский

Citations

415
Advances in COVID-19 mRNA vaccine development DOI Creative Commons
Enyue Fang, Xiaohui Liu, Miao Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 23, 2022

Abstract To date, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has determined 399,600,607 cases and 5,757,562 deaths worldwide. COVID-19 is a serious threat to human health globally. The World Health Organization (WHO) declared pandemic major public emergency. Vaccination most effective economical intervention for controlling spread of epidemics, consequently saving lives protecting population. Various techniques have been employed in development vaccines. Among these, messenger RNA (mRNA) vaccine drawing increasing attention owing its great application prospects advantages, which include short cycle, easy industrialization, simple production process, flexibility respond new variants, capacity induce better immune response. This review summarizes current knowledge on structural characteristics, antigen design strategies, delivery systems, industrialization potential, quality control, latest clinical trials real-world data mRNA vaccines as well technology. Current challenges future directions preventive infectious diseases are also discussed.

Language: Английский

Citations

409
Lipids and Lipid Derivatives for RNA Delivery DOI
Yuebao Zhang, Changzhen Sun, Chang Wang

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(20), P. 12181 - 12277

Published: July 19, 2021

RNA-based therapeutics have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown pathological genes, expression therapeutic proteins, and programmed gene editing. Due to the inherent instability negative-charges RNA molecules, can make most use delivery systems overcome biological barriers release payload into cytosol. Among different types systems, lipid-based particularly lipid nanoparticles (LNPs), been extensively studied due their unique properties, such as simple chemical synthesis components, scalable manufacturing processes LNPs, wide packaging capability. LNPs represent widely used for therapeutics, evidenced by clinical approvals three LNP-RNA formulations, patisiran, BNT162b2, mRNA-1273. This review covers recent advances lipids, derivatives, lipid-derived macromolecules over past several decades. We focus mainly on structures, synthetic routes, characterization, formulation methods, structure–activity relationships. also briefly describe current status representative preclinical studies trials highlight future opportunities challenges.

Language: Английский

Citations

400