Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes

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

Опубликована: Март 4, 2024

Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages use existing medications and hinders new drug development. One potential solution lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, lack accumulation. Here, we describe LNPs for efficacious mRNA delivery to organs in pregnant mice via several routes administration. In placenta, our lead LNP transfected trophoblasts, endothelial cells, immune with efficacy being structurally dependent on ionizable polyamine headgroup. Next, show that LNP-induced inflammatory responses affect expression compartment hinder neonatal Specifically, pro-inflammatory structures administration curtailed lymphoid an IL-1β-dependent manner. Further, immunogenic provoked infiltration adaptive cells into placenta restricted pup growth after birth. Together, results provide mechanism-based structural guidance design potent safe during pregnancy.

Язык: Английский

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Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

Nature Materials, Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Язык: Английский

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Inhaled mRNA nanoparticles dual-targeting cancer cells and macrophages in the lung for effective transfection

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(44)

Опубликована: Окт. 25, 2023

Messenger RNA (mRNA)–based therapeutics are transforming the landscapes of medicine, yet targeted delivery mRNA to specific cell types while minimizing off-target accumulation remains challenging for mRNA-mediated therapy. In this study, we report an innovative design a cationic lipid- and hyaluronic acid–based, dual-targeted nanoformulation that can display desirable stability efficiently transfect proteins into lung tissues. More importantly, optimized nanoparticles (NPs) not only accumulate primarily in tumor cells inflammatory macrophages after inhalation but also express any (e.g., p53 suppressor therapy, as well luciferase green fluorescence protein imaging examples study) achieve efficacious tissue transfection vivo. Overall, our findings provide proof-of-principle evidence use NPs homing up-regulate target tissues, which may hold great potential future development mRNA-based inhaled medicines or vaccines treating various lung-related diseases.

Язык: Английский

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Targeting materials and strategies for RNA delivery

Theranostics, Год журнала: 2023, Номер 13(13), С. 4667 - 4693

Опубликована: Янв. 1, 2023

RNA-based therapeutics have shown great promise in various medical applications, including cancers, infectious diseases, and metabolic diseases.The recent success of mRNA vaccines for combating the COVID-19 pandemic has highlighted value RNA drugs.However, one major challenges realizing full potential drugs is to deliver into specific organs tissues a targeted manner, which crucial achieving therapeutic efficacy, reducing side effects, enhancing overall treatment efficacy.Numerous attempts been made pursue targeting, nonetheless, lack clear guideline commonality elucidation hindered clinical translation drugs.In this review, we outline mechanisms action delivery systems summarize four key factors that influence targeting drugs.These include category vector materials, chemical structures vectors, administration routes, physicochemical properties they all notably contribute organ/tissue tropism.Furthermore, provide an overview main are currently trials, highlighting their design strategies tissue tropism applications.This review will aid understand principles systems, accelerating development future different diseases.

Язык: Английский

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Biomimetic noncationic lipid nanoparticles for mRNA delivery

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(51)

Опубликована: Дек. 11, 2023

Although the tremendous progress has been made for mRNA delivery based on classical cationic carriers, excess charge density of lipids was necessary to compress through electrostatic interaction, and with it comes inevitably adverse events including highly inflammatory cytotoxic effects. How develop disruptive technologies overcome nature remains a major challenge safe efficient delivery. Here, we prepared noncationic thiourea nanoparticles (NC-TNP) by strong hydrogen bonds interaction between groups NC-TNP phosphate mRNA, abandoning hidebound traditional force construct mRNA-cationic formulation. system simple, convenient, repeatable preparation technology showed negligible cytotoxicity side Furthermore, found that could escape recycling pathway inhibit egress internalized from intracellular compartment extracellular milieu which common fact in mRNA-LNP (lipid nanoparticles) Therefore, NC-TNP-encapsulated higher gene transfection efficiency vitro vivo than Unexpectedly, spleen targeting ability accumulation ratio (spleen/liver), compared LNP. Spleen-targeting exhibited high mRNA-encoded antigen expression elicited robust immune responses. Overall, our work establishes proof concept construction good safety profiles, efficiency, spleen-targeting induce permanent humoral cell-mediated immunity disease treatments.

Язык: Английский

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Messenger RNA-Based Therapeutics and Vaccines: What’s beyond COVID-19?

ACS Pharmacology & Translational Science, Год журнала: 2023, Номер 6(7), С. 943 - 969

Опубликована: Июль 3, 2023

With the rapid success in development of mRNA vaccines against COVID-19 and with a number mRNA-based drugs ahead pipelines, has catapulted to forefront drug research, demonstrating its substantial effectiveness broad range diseases. As recent global pandemic gradually fades, we cannot stop thinking about what world gained: realization validation power modern medicine. A significant amount research now been concentrated on developing vaccine platforms infectious immune diseases, cancer, other debilitating diseases demonstrated encouraging results. Here, based CAS Content Collection, provide landscape view current state, outline trends therapeutics vaccines, highlight some notable patents focusing therapeutics, delivery systems. Analysis disclosed also reveals highly investigated for treatments these medicines. Finally, information clinical trials. We hope this Review will be useful understanding knowledge field medicines assist efforts solve remaining challenges revolutionize treatment human

Язык: Английский

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Recent advances in drug delivery and targeting for the treatment of pancreatic cancer

Journal of Controlled Release, Год журнала: 2024, Номер 366, С. 231 - 260

Опубликована: Янв. 4, 2024

Язык: Английский

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Advances in the design and delivery of RNA vaccines for infectious diseases

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 213, С. 115419 - 115419

Опубликована: Авг. 5, 2024

RNA medicines represent a paradigm shift in treatment and prevention of critical diseases global significance, e.g., infectious diseases. The highly successful messenger (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed at record speed during the disease 2019 pandemic. A consequence this is exceptionally shortened vaccine development times, which combination with adaptability makes technology attractive for pandemic preparedness. Here, we review state art design delivery based on different modalities, including linear mRNA, self-amplifying RNA, trans-amplifying circular RNA. We provide an overview clinical pipeline diseases, present analytical procedures, are paramount characterizing quality attributes guaranteeing their quality, discuss future perspectives using to combat pathogens beyond SARS-CoV-2.

Язык: Английский

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Lipid Nanocarrier‐Based mRNA Therapy: Challenges and Promise for Clinical Transformation

Small, Год журнала: 2024, Номер 20(28)

Опубликована: Янв. 29, 2024

Abstract Due to the outbreak of novel coronavirus pneumonia, messenger RNA (mRNA) technology has attracted heated attention. A specific, safe, and efficient mRNA delivery system is needed. Lipid nanocarriers have become attractive carriers for due their high efficiency, few side effects, easy modification change structures functions. To achieve desired biological effect, lipid must reach designated location effective drug delivery. Therefore, effects composition on key properties are briefly reviewed. In addition, progress smart by changing summarized, importance component design structure emphasized. Subsequently, this review summarizes latest in nanocarrier‐based provides corresponding strategies its current challenges, putting forward valuable information future mRNA.

Язык: Английский

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Emerging strategies for nanomedicine in autoimmunity

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 207, С. 115194 - 115194

Опубликована: Фев. 10, 2024

Язык: Английский

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