Lipid Nanoparticle Composition Drives mRNA Delivery to the Placenta

Young, Rachel E.; Nelson, Katherine; Hofbauer, Samuel; Vijayakumar, Tara; Alameh, Mohamad-Gabriel; Weissman, Drew; Papachristou, Charalampos; Gleghorn, Jason P.; Riley, Rachel

doi:10.1101/2022.12.22.521490

Cited by 15 publications

(14 citation statements)

References 79 publications

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“…It is unknown how the placental tissue resists lipid nanoparticle uptake, despite direct exposure of fresh vaccine in the culture media. Different lipid nanoparticle composition has been recently shown to impact the degree of placental uptake 24 . We would anticipate that in vivo , the uptake of mRNA vaccines into the placenta would be less due to many other factors that likely contribute to vaccine degradation.…”

Section: Discussionmentioning

confidence: 99%

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants

González¹,

Li²,

Buarpung³

et al. 2023

Preprint

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Despite universal recommendations for COVID-19 mRNA vaccination in pregnancy, uptake has been lower than desired. There have been limited studies of the direct impact of COVID-19 mRNA vaccine exposure in human placental tissue. Using a primary human villous explant model, we investigated the uptake of two common mRNA vaccines (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna), and whether exposure altered villous cytokine responses. Explants derived from second or third trimester chorionic villi were incubated with vaccines at supraphysiologic concentrations and analyzed at two time points. We observed minimal uptake of mRNA vaccines in placental explants by in situ hybridization and quantitative RT-PCR. No specific or global cytokine response was elicited by either of the mRNA vaccines in multiplexed immunoassays. Our results suggest that the human placenta does not readily absorb the COVID-19 mRNA vaccines nor generate a significant inflammatory response after exposure.

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Section: Discussionmentioning

confidence: 99%

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants

González¹,

Li²,

Buarpung³

et al. 2023

Preprint

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“…Starting with 43 papers that report on luciferase mRNA LNPs as of April 2023, we excluded 29 papers that either (i) added a fifth component (either for stability or targeting purposes), (ii) modified other lipid components (such as helper lipid or cholesterol), or (iii) tested only in vivo. With these exclusions, the final dataset included 2,332 LNPs from 14 different papers across 10 different labs [10][11][12][13][14][15][35][36][37][38][39][40][41][42] .…”

Section: Methodsmentioning

confidence: 99%

Applying machine learning to identify ionizable lipids for nanoparticle-mediated delivery of mRNA

Lewis,

Beck,

Ghosh

2023

Preprint

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AbstractmRNA lipid nanoparticles (LNPs) have a tremendous potential to treat, cure, or prevent many diseases. To identify promising candidates for each application, most studies screen dozens to hundreds of formulations with ionizable lipids synthesized using a single type of chemistry. However, this technique leaves the ionizable lipids synthesized through multi-step chemistries underexplored. This gap in the repertoire of structures is of particular significance because it affects the screening of analogs that are structurally similar to SM-102 and ALC-0315, the ionizable lipids used to formulate the clinically approved mRNA LNP COVID-19 vaccines. Herein, we address this by employing LightGBM, a machine learning algorithm, to reduce the burden of screening these types of ionizable lipids by learning from the breadth and diversity of lipids that have already been tested. We first evaluate the ability of LightGBM to predict LNP potency across heterogeneous chemistries from different studies to achieve an R2of 0.94. After establishing the predictive capacity of the model, we then identify the number of outside carbons in the ionizable lipid as the most important factor contributing to transfection efficiency. From this finding, we subsequently apply the algorithm to predict the effect of formulating nanoluciferase mRNA LNPs using analogs of SM-102 and ALC-0315 with small changes in the number of outside carbons on luciferase activity in HEK293T cells and achieve an R2of 0.83. Importantly, this correlation encompasses novel lipids not included within the database used to train the algorithm. Overall, this study demonstrates the potential of machine learning to accelerate the development of new ionizable lipids by simplifying the screening process.

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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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Lipid Nanoparticle Composition Drives mRNA Delivery to the Placenta

Cited by 15 publications

References 79 publications

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants

Applying machine learning to identify ionizable lipids for nanoparticle-mediated delivery of mRNA

Messenger RNA Therapy for Female Reproductive Health

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