Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect DOI Creative Commons
Tianjiao Wang, Youhong Tang,

Yuandong Tao

и другие.

Deleted Journal, Год журнала: 2024, Номер 2(1)

Опубликована: Янв. 1, 2024

Abstract Over the two decades, RNA drugs have gradually made their way from bench to bed. Initially, was not an ideal drug since molecules degrade easily and a relatively short half‐life in circulation system. Nevertheless, chemical modification extended of recent years, which makes new star discovery industry. hold many properties that facilitate application as therapeutic drugs. RNAs could fold form complex conformations bind proteins, small molecules, or other nucleic acids, some even catalytic centers. Protein‐encoding are carriers genetic information DNA ribosomes, various types non‐coding cooperate transcription translation through mechanisms. To date, three mainstream therapies drawn widespread attention: (1) messenger encodes proteins vaccine antigens; (2) interfering RNA, microRNA (miRNA), antisense oligonucleotides inhibit activity pathogenic RNAs; (3) aptamers regulate protein activity. Here, we summarized current research perspectives therapies, may provide innovative highlights for cancer therapy.

Язык: Английский

Quality assessment of LNP-RNA therapeutics with orthogonal analytical techniques DOI Creative Commons
Jérémie Parot, Dóra Méhn,

Hanna Jankevics

и другие.

Journal of Controlled Release, Год журнала: 2024, Номер 367, С. 385 - 401

Опубликована: Фев. 1, 2024

The availability of analytical methods for the characterization lipid nanoparticles (LNPs) in-vivo intracellular delivery nucleic acids is critical fast development innovative RNA therapies. In this study, protocols to measure (i) chemical composition, (ii) drug loading, (iii) particle size, concentration, and stability as well (iv) structure morphology were evaluated compared based on a comprehensive strategy linking key physical properties in-vitro efficacy toxicity. Furthermore, measurement assessed either by testing reproducibility robustness same technique in different laboratories, or correlative approach, comparing results attribute with orthogonal techniques. measurements described here will have an important role during formulation determining robust quality attributes ultimately supporting assessment these therapeutics.

Язык: Английский

Процитировано

24
Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues DOI Creative Commons
Yulia Eygeris, Mohit Gupta, Jeonghwan Kim

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(11)

Опубликована: Март 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.

Язык: Английский

Процитировано

21
Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles DOI
Jacob L. Thelen, Wellington Leite, Volker S. Urban

и другие.

ACS Nano, Год журнала: 2024, Номер 18(2), С. 1464 - 1476

Опубликована: Янв. 4, 2024

The mRNA technology has emerged as a rapid modality to develop vaccines during pandemic situations with the potential protect against endemic diseases. success of in producing an antigen is dependent on ability deliver cells using vehicle, which typically consists lipid nanoparticle (LNP). Self-amplifying (SAM) synthetic platform that, besides encoding for interest, includes replication machinery amplification cells. Thus, SAM can generate many copies and prolong expression lower doses than those required conventional mRNA. This work describes morphology LNPs containing encapsulated (SAM LNPs), being three four times larger We show evidence that changes its conformational structure when LNPs, becoming more compact free form. A characteristic "bleb" observed lipid-rich core aqueous RNA-rich core, both surrounded by DSPC-rich shell. used SANS SAXS data confirm prevalent LNP two-core compartments where components are heterogeneously distributed between two cores capped cylinder core–shell model interior was built capture overall LNP. These findings provide bleb two-compartment structures be representative highlight need additional studies elucidate role spherical morphologies, their mechanisms formation, parameters lead particular rational design delivery.

Язык: Английский

Процитировано

20
Lipid shape and packing are key for optimal design of pH-sensitive mRNA lipid nanoparticles DOI
Giulio Tesei, Ya‐Wen Hsiao, Aleksandra P. Dabkowska

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(2)

Опубликована: Янв. 4, 2024

The ionizable-lipid component of RNA-containing nanoparticles controls the pH-dependent behavior necessary for an efficient delivery cargo—the so-called endosomal escape. However, it is still empirical exercise to identify optimally performing lipids. Here, we study two well-known ionizable lipids, DLin-MC3-DMA and DLin-DMA using a combination experiments, multiscale computer simulations, electrostatic theory. All-atom molecular dynamics experimentally measured polar headgroup p K values, are used develop coarse-grained representation which enables investigation lipid (LNPs) through Monte Carlo in absence presence RNA molecules. Our results show that charge state lipids determined by interplay between shape chemistry, providing explanation similar ionization observed with values about one-pH-unit apart. pH dependence significantly influenced RNA, whereby neutrality achieved imparting finite constant per at intermediate values. simulation supported measurements α-carbon 13 C-NMR chemical shifts eGFP mRNA LNPs both various conditions. Further, evaluate applicability mean-field Poisson–Boltzmann theory capture these phenomena.

Язык: Английский

Процитировано

20
Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect DOI Creative Commons
Tianjiao Wang, Youhong Tang,

Yuandong Tao

и другие.

Deleted Journal, Год журнала: 2024, Номер 2(1)

Опубликована: Янв. 1, 2024

Abstract Over the two decades, RNA drugs have gradually made their way from bench to bed. Initially, was not an ideal drug since molecules degrade easily and a relatively short half‐life in circulation system. Nevertheless, chemical modification extended of recent years, which makes new star discovery industry. hold many properties that facilitate application as therapeutic drugs. RNAs could fold form complex conformations bind proteins, small molecules, or other nucleic acids, some even catalytic centers. Protein‐encoding are carriers genetic information DNA ribosomes, various types non‐coding cooperate transcription translation through mechanisms. To date, three mainstream therapies drawn widespread attention: (1) messenger encodes proteins vaccine antigens; (2) interfering RNA, microRNA (miRNA), antisense oligonucleotides inhibit activity pathogenic RNAs; (3) aptamers regulate protein activity. Here, we summarized current research perspectives therapies, may provide innovative highlights for cancer therapy.

Язык: Английский

Процитировано

20