RNA-based therapeutics have emerged as a promising method in modern medicine, offering potential treatments for a wide range of diseases (1). However, their effectiveness has been limited by several challenges, including sensitivity to degradation, short-lived effects, and difficulties in safely and efficiently delivering RNA molecules to target cells. The targeted delivery of RNA using lipid nanoparticles (LNPs) has been a particular bottleneck in this field. A recent breakthrough study by researchers from the University of Pennsylvania has demonstrated significant progress in addressing these challenges, specifically in the context of treating pre-eclampsia (2). The study, published in Nature, demonstrates the successful targeted delivery of Vascular Endothelial Growth Factor (VEGF) mRNA to the placenta in pregnant mice using modified LNPs.

What is pre-eclampsia

Pre-eclampsia affects 5% of human pregnancies and currently has no specific treatment beyond managing symptoms. The first sign of preeclampsia is typically high blood pressure. Other symptoms may include protein in urine (proteinuria), headache, nausea, vomiting, vision changes, shortness of breath, and abdominal pain (3). One of the features is an abnormal vascular system (4). If left untreated, preeclampsia can lead to eclampsia. Eclampsia’s complications can include risk of coma and a threat to the health of both mother and baby (3).

Innovative strategies for pre-eclampsia treatment: leveraging VEGF and lipid nanoparticles

VEGF counteracts the pathological effects of excessive sFlt-1 protein in pre-eclampsia.

A basic contributing cause to the pathology of pre-eclampsia is believed to be a defect in the normal maintenance and production of blood vesicles. Vascular endothelial growth factor (VEGF) is responsible for the growth of new blood vessels. With inhibition of VEGF activity, normal development of blood vessels and proper vascular function does not occur within the placenta. The cellular receptor for VEGF is Feline McDonough Sarcoma (fms)-like tyrosine kinase-1 (Flt-1). A soluble form, sFlt-1, inhibits the biological effects of VEGF and occurs especially in the placenta. The elevated sFlt-1 levels in pre-eclampsia are significantly higher than in normal pregnancies, with studies showing almost five times higher placental and serum sFlt-1 levels in women with pre-eclampsia compared to normotensive pregnant women (5).

The delivery of VEGF counteracts the effects of elevated sFlt-1 in pre-eclampsia (5). The sFlt-1 acts as an antagonist to pro-angiogenic molecules such as vascular endothelial growth factor (VEGF), blocking the development of new blood vessels. By increasing VEGF production, restoration of proper vascular function and angiogenesis in the placenta (3.4) can occur.

Preclinical research efforts for treating pre-eclampsia include recombinant VEGF protein therapies, viral-vector-mediated VEGF overexpression, and siRNA-based gene silencing to reduce soluble fms-like tyrosine kinase-1 (sFlt-1) level (5). While these approaches show promise, recombinant proteins and siRNAs face pharmacokinetic and delivery challenges, and viral vectors are limited by issues such as immunogenicity, non-specific targeting, and manufacturing constraints. Ionizable lipid nanoparticles (LNPs) have gained clinical success as a non-viral platform for nucleic acid delivery. The FDA has approved therapies like Onpattro (6) for hATTR, an amyloidosis caused by a mutation in the transthyretin (TTR) gene, and mRNA COVID-19 vaccines (7). While LNPs traditionally target the liver via apolipoprotein E (ApoE) binding and internalization, recent efforts aim to expand their use for extrahepatic delivery, including placental mRNA delivery. To address the limitations of in vitro screening, a high-throughput in vivo LNP screening method is used to improve the design of targeted delivery of LNPs to the placenta.

Development and validation of placenta-targeted LNPs

The Swingle paper (2) used mRNA for VEGF encapsulated in LNP to treat murine pre-eclampsia. High-throughput in vivo LNP screening identified specific polyamine cores that facilitated efficient extrahepatic delivery of LNPs to the placenta. The study also explored the effects of pre-eclampsia on the delivery and biodistribution of a selected LNP encapsulating luciferase mRNA in pregnant mice using an inflammation-induced pre-eclampsia model, finding significant liver accumulation and increased placental delivery in pre-eclamptic mice compared to healthy controls.

Mechanism of placental LNP delivery

The study explored the mechanism of LNP-mediated targeted mRNA delivery to the placenta, proposing that its ionizable lipid (C14-494) facilitates β2-glycoprotein I (β2-GPI) binding, creating a β2-GPI-rich protein complex that enhances placental delivery. Experimental comparisons between placenta-targeting and liver-targeting LNPs supported this hypothesis. The β2-GPI knockdown mouse study demonstrated that reducing β2-GPI levels significantly reduces placental delivery of the LNPs, underscoring β2-GPI’s role in LNP-mediated placental delivery. These findings emphasize β2-GPI binding as a critical factor for placental specificity and highlight the potential of customizing protein complex to improve tissue-specific drug delivery.

VEGF mRNA LNP therapy for pre-eclampsia: promising results from mouse model studies

The study evaluated VEGF mRNA-loaded LNP 55 as a therapeutic for pre-eclampsia in both inflammation-induced and a hypoxia-induced mouse models. In the inflammation-induced model, placenta-targeting VEGF mRNA LNP demonstrated improved outcomes, including reduced maternal hypertension, increased fetal and placental weights, decreased inflammatory cytokines, and enhanced placental vasculature. In the hypoxia-induced model, the VEGF mRNA LNP reduced blood pressure and sFlt-1 levels, improved fetal and placental weight distributions, and alleviated liver and kidney damage, outperforming a liver-targeting LNP in placental efficacy. Both models showcased the placenta-targeting VEGF mRNA LNP’s ability to restore placental function and alleviate pre-eclampsia symptoms with minimal systemic inflammation or toxicity.

Conclusion

The study underscores the transformative potential of lipid nanoparticle (LNP)-mediated RNA delivery, showcasing VEGF mRNA-loaded LNPs as a targeted therapeutic for pre-eclampsia, a condition with limited treatment options. Through high-throughput in vivo screening and advanced LNP design, researchers developed placenta-specific delivery systems that demonstrated remarkable efficacy in preclinical models. The targeted delivery of VEGF mRNA via LNPs effectively reduced maternal hypertension, restored placental function, and mitigated systemic complications such as inflammation, liver damage, and kidney dysfunction. Furthermore, the identification of the β2-glycoprotein I (β2-GPI)-mediated mechanism of placental selectivity highlights the critical role of customizing protein complex to achieve precise tissue targeting. These findings represent a major advancement in LNP and RNA-based therapies, paving the way for safer and more efficient treatments for pre-eclampsia and other complex medical conditions.

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References

  1. Zhu et al, RNA-based therapeutics: an overview and prospectus. Cell Death & Disease, vol. 13, article 644 (2022)
  2. Swingle et al.  Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia. Nature volume 637, pages412–421 (2025)
  3. Dulay, A. T. Preeclampsia and Eclampsia, MSD (Merck) Manual Professional Version, 2024.
  4. Enkhmaa et al. Preeclampsia and Vascular Function: A Window to Future Cardiovascular Disease Risk. J Womens Health vol 25 ,284 (2016). doi: 10.1089/jwh.2015.5414 PMCID: PMC4790201 PMID: 26779584
  5. Woods et al. Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. Hypertension 57,94 (2011).
  6. Urits et al. A Review of Patisiran (ONPATTRO®) for the Treatment of Polyneuropathy in People with Hereditary Transthyretin Amyloidosis. Neurol Ther vol 9, 301 (2020). . doi: 10.1007/s40120-020-00208-1
  7. Mansi et al. Navigating the Evolving Landscape of COVID-19: Strategies to Increase Vaccine Confidence and Improve Vaccination Rates in the United States. Vaccines vol 12, 1072 (2024). doi: 10.3390/vaccines12091072