دورية أكاديمية
أعرض في EDS

A Lung-Expressing mRNA Delivery Platform with Tunable Activity in Hypoxic Environments.

التفاصيل البيبلوغرافية
العنوان: A Lung-Expressing mRNA Delivery Platform with Tunable Activity in Hypoxic Environments.
المؤلفون: Tiwade PB; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Ma Y; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., VanKeulen-Miller R; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Fenton OS; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
المصدر: Journal of the American Chemical Society [J Am Chem Soc] 2024 Jun 26; Vol. 146 (25), pp. 17365-17376. Date of Electronic Publication: 2024 Jun 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]
مواضيع طبية MeSH: RNA, Messenger*/genetics , RNA, Messenger*/metabolism , RNA, Messenger*/administration & dosage , Lung*/metabolism, Humans ; Animals ; Mice ; Nanoparticles/chemistry ; Cell Hypoxia ; Hypoxia/metabolism
مستخلص: Messenger RNA (mRNA) delivery platforms often facilitate protein expression in the liver following intravenous injection and have been optimized for use in normally oxygenated cells (21% O 2 atmosphere). However, there is a growing need for mRNA therapy in diseases affecting non-liver organs, such as the lungs. Additionally, many diseases are characterized by hypoxia (<21% O 2 atmosphere), a state of abnormally low oxygenation in cells and tissues that can reduce the efficacy of mRNA therapies by upwards of 80%. Here, we report a Tu nable L ung- E xpressing Nanoparticle P latform ( TULEP ) for mRNA delivery, whose properties can be readily tuned for optimal expression in hypoxic environments. Briefly, our study begins with the synthesis and characterization of a novel amino acrylate polymer that can be effectively complexed with mRNA payloads into TULEP s. We study the efficacy and mechanism of mRNA delivery using TULEP , including analysis of the cellular association, endocytosis mechanisms, endosomal escape, and protein expression in a lung cell line. We then evaluate TULEP under hypoxic conditions and address hypoxia-related deficits in efficacy by making our system tunable with adenosine triphosphate (ATP). Finally, we conclude our study with an in vivo analysis of mRNA expression, biodistribution, and tolerability of the TULEP platform in mice. In presenting these data, we hope that our work highlights the utility of TULEP s for tunable and effective mRNA delivery while more broadly highlighting the utility of considering oxygen levels when developing mRNA delivery platforms.
المشرفين على المادة: 0 (RNA, Messenger)
تواريخ الأحداث: Date Created: 20240614 Date Completed: 20240626 Latest Revision: 20240626
رمز التحديث: 20240626
DOI: 10.1021/jacs.4c04565
PMID: 38874565
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-5126
DOI:10.1021/jacs.4c04565