Surface engineering of lipid nanoparticles: targeted nucleic acid delivery and beyond DOI Creative Commons
Yi Lin, Qiang Cheng, Tuo Wei

et al.

Biophysics Reports, Journal Year: 2023, Volume and Issue: 9(5), P. 255 - 255

Published: Jan. 1, 2023

Harnessing surface engineering strategies to functionalize nucleic acid-lipid nanoparticles (LNPs) for improved performance has been a hot research topic since the approval of first siRNA drug, patisiran, and two mRNA-based COVID-19 vaccines, BNT162b2 mRNA-1273. Currently, efforts have mainly made construct targeted LNPs organ- or cell-type-specific delivery acid drugs by conjugation with various types ligands. In this review, we describe acid-LNPs, considering ligand types, chemistries, incorporation methods. We then outline general purification characterization techniques that are frequently used following step emphasize specific certain Next, comprehensively summarize currently accessible organs cell as well other applications engineered LNPs. Finally, provide considerations formulating discuss challenges successfully translating "proof concept" from laboratory into clinic. believe addressing these could accelerate development surface-engineered beyond.

Language: Английский

Strategies to reduce the risks of mRNA drug and vaccine toxicity DOI
Dimitrios Bitounis, Eric Jacquinet, Maximillian A. Rogers

et al.

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(4), P. 281 - 300

Published: Jan. 23, 2024

Language: Английский

Citations

63
Liquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection DOI Creative Commons
Roy Pattipeiluhu, Ye Zeng,

Marco M. R. M. Hendrix

et al.

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

Published: Feb. 12, 2024

Abstract Efficient cytosolic delivery of RNA molecules remains a formidable barrier for therapeutic strategies. Lipid nanoparticles (LNPs) serve as state-of-the-art carriers that can deliver intracellularly, exemplified by the recent implementation several vaccines against SARS-CoV-2. Using bottom-up rational design approach, we assemble LNPs contain programmable lipid phases encapsulating small interfering (siRNA). A combination cryogenic transmission electron microscopy, tomography and small-angle X-ray scattering reveals form inverse hexagonal structures, which are present in liquid crystalline nature within LNP core. Comparison with lamellar presence enhances intracellular silencing efficiency over structures. We then demonstrate exhibit an situ transition from to phase upon interaction anionic membranes, whereas containing pre-programmed bypass this more efficient one-step mechanism, explaining increased effect. This defined structures aids understanding nano-bio interface adds substantial value design, optimization use.

Language: Английский

Citations

31
Evolution of the structure of lipid nanoparticles for nucleic acid delivery: From in situ studies of formulation to colloidal stability DOI Creative Commons
Jennifer Gilbert, Federica Sebastiani, Marianna Yanez Arteta

et al.

Journal of Colloid and Interface Science, Journal Year: 2024, Volume and Issue: 660, P. 66 - 76

Published: Jan. 5, 2024

The development of lipid nanoparticle (LNP) based therapeutics for delivery RNA has triggered the advance new strategies formulation, such as high throughput microfluidics precise mixing components into well-defined particles. In this study, we have characterised structure LNPs throughout formulation process using in situ small angle x-ray scattering microfluidic chip, then by sampling subsequent dialysis process. final was investigated with (SAXS) and neutron (SANS) scattering, dynamic light (DLS) cryo-TEM. effect on a benchmark composition containing different cargos: calf thymus DNA (DNA) two model mRNAs, polyadenylic acid (polyA) polyuridylic (polyU). LNP evolved during channel, however only fully developed dialysis. colloidal stability affected type incorporated nucleic acids (NAs) decreased degree base-pairing, polyU induced extensive particle aggregation. main NA peak SAXS data were similar, repeat distance increasing from polyU

Language: Английский

Citations

25
Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery DOI Creative Commons
Markéta Paloncýová, Mariana Valério, Ricardo Nascimento dos Santos

et al.

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Lipid-mediated delivery of active pharmaceutical ingredients (API) opened new possibilities in advanced therapies. By encapsulating an API into a lipid nanocarrier (LNC), one can safely deliver APIs not soluble water, those with otherwise strong adverse effects, or very fragile ones such as nucleic acids. However, for the rational design LNCs, detailed understanding composition-structure-function relationships is missing. This review presents currently available computational methods LNC investigation, screening, and design. The state-of-the-art physics-based approaches are described, focus on molecular dynamics simulations all-atom coarse-grained resolution. Their strengths weaknesses discussed, highlighting aspects necessary obtaining reliable results simulations. Furthermore, machine learning, i.e., data-based approach to lipid-mediated introduced. data produced by experimental theoretical provide valuable insights. Processing these help optimize LNCs better performance. In final section this Review, computer reviewed, specifically addressing compatibility

Language: Английский

Citations

2
pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function DOI Creative Commons
Julian Philipp, Aleksandra P. Dabkowska, Anita Reiser

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(50)

Published: Dec. 6, 2023

Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism pH-dependent response is believed to cause endosomal release LNPs not well understood. Here, we show eGFP (enhanced green fluorescent protein) protein expression in mouse liver mediated by lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery mRNA per cell all fractions isolated. We hypothesize three CIL-LNPs react differently pH changes hence study structure CIL/chol bulk phases water. Using synchrotron X-ray scattering a sequence ordered mesophases with lowering values observed. These isotropic inverse micellar, cubic Fd3m hexagonal [Formula: see text] bicontinuous Pn3m symmetry. If polyadenylic acid, as surrogate, added CIL/chol, excess coexists condensed nucleic acid phase. The next-neighbor distance phase shows discontinuity at micellar transition occurring 6 distinctly larger spacing hydration vs. KC2. In LNPs, showed internal spacing, retarded onset reduced level DD-LNP-mediated vitro compared Our data suggest pH-driven Fd3m-[Formula: hallmark CIL-specific differences LNP efficacy.

Language: Английский

Citations

41
Process Robustness in Lipid Nanoparticle Production: A Comparison of Microfluidic and Turbulent Jet Mixing DOI
Matthew N. O’Brien, António Pedro Costa,

Yareli Maciel Cebrero

et al.

Molecular Pharmaceutics, Journal Year: 2023, Volume and Issue: 20(8), P. 4285 - 4296

Published: July 18, 2023

The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development new technologies to manufacture LNPs. As emerge, researchers must determine which assess how perform comparative evaluations. In this article, we use a quality-by-design approach systematically investigate mixer technology used form LNPs influences LNPstructure. Specifically, coaxial turbulent jet staggered herringbone microfluidic were compared via matched formulation process conditions. A full-factorial design-of-experiments study with three factors levels was executed each compare robustness in production antisense oligonucleotide (ASO) ASO-LNPs generated consistently smaller, had narrower particle size distribution, higher ASO encapsulation as mixer, but greater variation internal structure less ordered cores. subset replicated mRNA-LNPs comparable trends encapsulation, more frequent bleb features produced by mixer. design here provides road map may different (or changes broadly) such studies can inform manufacturing control strategies.

Language: Английский

Citations

24
Advances in the design and delivery of RNA vaccines for infectious diseases DOI Creative Commons
Abhijeet Lokras,

Thomas Rønnemoes Bobak,

Saahil Baghel

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 213, P. 115419 - 115419

Published: Aug. 5, 2024

RNA medicines represent a paradigm shift in treatment and prevention of critical diseases global significance, e.g., infectious diseases. The highly successful messenger (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed at record speed during the disease 2019 pandemic. A consequence this is exceptionally shortened vaccine development times, which combination with adaptability makes technology attractive for pandemic preparedness. Here, we review state art design delivery based on different modalities, including linear mRNA, self-amplifying RNA, trans-amplifying circular RNA. We provide an overview clinical pipeline diseases, present analytical procedures, are paramount characterizing quality attributes guaranteeing their quality, discuss future perspectives using to combat pathogens beyond SARS-CoV-2.

Language: Английский

Citations

11
mRNA lipid nanoparticle formulation, characterization and evaluation DOI
Yutian Ma,

Rachel VanKeulen-Miller,

Owen S. Fenton

et al.

Nature Protocols, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Language: Английский

Citations

1
Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines DOI Creative Commons
Yu Wu, Jieli Wang,

Yuru Deng

et al.

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(14)

Published: Feb. 22, 2024

Plasmalogens (vinyl-ether phospholipids) are an emergent class of lipid drugs against various diseases involving neuro-inflammation, oxidative stress, mitochondrial dysfunction, and altered metabolism. They can activate neurotrophic neuroprotective signaling pathways but low bioavailabilities limit their efficiency in curing neurodegeneration. Here, liquid crystalline nanoparticles (LNPs) created for the protection non-invasive intranasal delivery purified scallop-derived plasmalogens. The vivo results with a transgenic mouse Parkinson's disease (PD) model (characterized by motor impairments α-synuclein deposition) demonstrate crucial importance LNP composition, which determines self-assembled nanostructure type. Vesicle hexosome nanostructures small-angle X-ray scattering) display different efficacy nanomedicine-mediated recovery function, balance, transcriptional regulation (e.g., reduced neuro-inflammation PD pathogenic gene expression). Intranasal vesicular hexosomal plasmalogen-based treatment leads to improvement behavioral symptoms downregulation Il6, Il33, Tnfa genes. Moreover, RNA-sequencing lipidomic analyses establish dramatic effect nanomedicines on amelioration, metabolism, type number responsive transcripts that may be implicated neuroregeneration.

Language: Английский

Citations

8
Oxidized mRNA Lipid Nanoparticles for In Situ Chimeric Antigen Receptor Monocyte Engineering DOI Creative Commons

Alvin J. Mukalel,

Alex G. Hamilton, Margaret M. Billingsley

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(27)

Published: March 5, 2024

Abstract Chimeric antigen receptor (CAR) monocyte and macrophage therapies are promising solid tumor immunotherapies that can overcome the challenges facing conventional CAR T cell therapy. mRNA lipid nanoparticles (mRNA‐LNPs) offer a viable platform for in situ engineering of monocytes with transient tunable expression to reduce off‐tumor toxicity streamline manufacturing. However, identifying LNPs tropism intracellular delivery potency is difficult using traditional screening techniques. Here, ionizable design high‐throughput vivo utilized identify new class oxidized innate monocytes. A library (oLNPs) unoxidized (uLNPs) synthesized evaluate immune cells. oLNPs demonstrate notable differences morphology, ionization energy, p K , thereby enhancing human macrophages, but not Subsequently, DNA barcodes identifies an oLNP formulation, C14‐O2, In proof‐of‐concept study, C14‐O2 LNP used engineer functional CD19‐CAR robust B aplasia (45%) healthy mice. This work highlights utility as macrophages/monocytes

Language: Английский

Citations

7