Ionizable Lipid Nanoparticles for <i>In Vivo</i> mRNA Delivery to the Placenta during Pregnancy

Swingle, Kelsey L.; Safford, Hannah C.; Geisler, Hannah C.; Hamilton, Alex G.; Thatte, Ajay S.; Billingsley, Margaret M.; Joseph, Ryann A; Mrksich, Kaitlin; Padilla, Marshall S.; Ghalsasi, Aditi A.; Alameh, Mohamad-Gabriel; Weissman, Drew; Mitchell, Michael J.

doi:10.1021/jacs.2c12893

Cited by 77 publications

(47 citation statements)

References 71 publications

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“…LNP carriers would be ideal carriers as they contain PEG, which has been shown to increase uptake into placental cells more readily than other polymers . For a disease-relevant application of placental delivery of mRNA LNPs, maternal tail vein injection of mRNA LNPs encoding PlGF and VEGF (Figure A–D) both caused vasodilation of the placenta in murine models.…”

Section: Localized Delivery Of Rna For Women’s Healthmentioning

confidence: 99%

Messenger RNA Therapy for Female Reproductive Health

VanKeulen-Miller,

Fenton

2024

Mol. Pharmaceutics

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Female reproductive health has traditionally been an underrepresented area of research in the drug delivery sciences. This disparity is also seen in the emerging field of mRNA therapeutics, a class of medicines that promises to treat and prevent disease by upregulating protein expression in the body. Here, we review advances in mRNA therapies through the lens of improving female reproductive health. Specifically, we begin our review by discussing the fundamental structure and biochemical modifications associated with mRNA-based drugs. Then, we discuss various packaging technologies, including lipid nanoparticles, that can be utilized to protect and transport mRNA drugs to target cells in the body. Last, we conclude our review by discussing the usage of mRNA therapy for addressing pregnancy-related health and vaccination against sexually transmitted diseases in women. Of note, we also highlight relevant clinical trials using mRNA for female reproductive health while also providing their corresponding National Clinical Trial identifiers. In undertaking this review, our aim is to provide a fundamental background understanding of mRNA therapy and its usage to specifically address female health issues with an overarching goal of providing information toward addressing gender disparity in certain aspects of health research.

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Section: Localized Delivery Of Rna For Women’s Healthmentioning

confidence: 99%

Messenger RNA Therapy for Female Reproductive Health

VanKeulen-Miller,

Fenton

2024

Mol. Pharmaceutics

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“…RNA Entrapment and Concentration: Entrapment of RNA was assessed using a modified Quant-iT RiboGreen assay as described previously. [46] Briefly, LNP stocks were diluted 100× in tris-EDTA (TE) buffer or in 0.1% (v/v) Triton X-100 (MilliporeSigma) in TE buffer. 100 μL of diluted LNP was plated in quadruplicate in a flat-bottom, black-walled 96-well plate.…”

Section: Eperimental Sectionmentioning

confidence: 99%

Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering

Hamilton,

Swingle,

Joseph

et al. 2023

Adv Healthcare Materials

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The programmed cell death protein 1 (PD‐1) signaling pathway is a major source of dampened T cell activity in the tumor microenvironment (TME). While clinical approaches to inhibiting the PD‐1 pathway using antibody blockade have been broadly successful, these approaches lead to widespread PD‐1 suppression, increasing the risk of autoimmune reactions. This work reports the development of an ionizable lipid nanoparticle (LNP) platform for simultaneous therapeutic mRNA expression and RNA interference (RNAi)‐mediated transient gene knockdown in T cells. In developing this platform, interesting interactions were observed between the two RNA cargoes when co‐encapsulated, leading to improved expression and knockdown characteristics compared to delivering either cargo alone. This messenger RNA (mRNA)/small interfering RNA (siRNA) co‐delivery platform was adopted to deliver chimeric antigen receptor (CAR) mRNA and siRNA targeting PD‐1 to primary human T cells ex vivo and strong CAR expression and PD‐1 knockdown were observed without apparent changes to overall T cell activation state. This delivery platform shows great promise for transient immune gene modulation for a number of immunoengineering applications, including in the development of improved cancer immunotherapies.This article is protected by copyright. All rights reserved

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“…429 Additionally, Swingle and colleagues recently reported on a systematic study in which they screened lipid NPs with differing ionizable lipid components for both their mRNA loading and their placental targeting. 455 While lipid NPs have commonly been used for liver accumulation for, among others, vaccination purposes, oxygen-containing lipids were found to significantly increase extrahepatic delivery towards the placenta. In a similar fashion, systematically varying the molar ratios of C12-200, DOPE, cholesterol and PEG allowed optimal lipid NP design for maximizing placental accumulation.…”

Section: Box 4: Placental Barrier Characteristicsmentioning

confidence: 99%