Polyphenolic Nanoparticle Platforms (PARCELs) for In Vitro and In Vivo mRNA Delivery

Nano Letters, Journal Year: 2024, Volume and Issue: 24(20), P. 6092 - 6101

Published: May 10, 2024

Despite their successful implementation in the COVID-19 vaccines, lipid nanoparticles (LNPs) still face a central limitation delivery of mRNA payloads: endosomal trapping. Improving upon this inefficiency could afford improved drug systems, paving way toward safer and more effective mRNA-based medicines. Here, we present

Language: Английский

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

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(25), P. 17365 - 17376

Published: June 14, 2024

Messenger RNA (mRNA) delivery platforms often facilitate protein expression in the liver following intravenous injection and have been optimized for use normally oxygenated cells (21% O2 atmosphere). However, there is a growing need mRNA therapy diseases affecting non-liver organs, such as lungs. Additionally, many are characterized by hypoxia (<21% atmosphere), state of abnormally low oxygenation tissues that can reduce efficacy therapies upwards 80%. Here, we report Tunable Lung-Expressing Nanoparticle Platform (TULEP) delivery, whose properties be readily tuned optimal hypoxic environments. Briefly, our study begins with synthesis characterization novel amino acrylate polymer effectively complexed payloads into TULEPs. We mechanism using TULEP, including analysis cellular association, endocytosis mechanisms, endosomal escape, lung cell line. then evaluate TULEP under conditions address hypoxia-related deficits making system tunable adenosine triphosphate (ATP). Finally, conclude an vivo expression, biodistribution, tolerability platform mice. In presenting these data, hope work highlights utility TULEPs effective while more broadly highlighting considering oxygen levels when developing platforms.

Language: Английский

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Non-Viral RNA Therapies for Non-Small Cell Lung Cancer and Their Corresponding Clinical Trials

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Ribonucleic acid (RNA)-based therapies represent a promising class of drugs for the treatment non-small cell lung cancer (NSCLC) due to their ability modulate gene expression. Therapies leveraging small interfering RNA (siRNA), messenger (mRNA), microRNA (miRNA), and antisense oligonucleotides (ASOs) offer various advantages over conventional treatments, including target specific genetic mutations potential personalized medicine approaches. However, clinical translation these therapeutics NSCLC faces challenges in delivery immunogenicity, negative charge, large size, which can be mitigated with platforms. In this review, we provide description pathophysiology an overview RNA-based therapeutics, specifically highlighting application NSCLC. We discuss relevant classes therapeutic then non-viral strategies such as lipid- polymer-based nanoparticles that have been developed address issues preclinical models. Furthermore, summary table trials leverage [which includes National Clinical Trial (NCT) numbers] highlight current progress also how integrated existing modalities enhance efficacy improve patient outcomes. Overall, aim tackle while showcasing RNA's next-generation therapy treatment.

Language: Английский

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A Metabolite Co-Delivery Strategy to Improve mRNA Lipid Nanoparticle Delivery

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

Lipid nanoparticles (LNPs) effectively protect mRNA and facilitate its entry into target cells for protein synthesis. Despite these successes, cellular alone may not be enough optimal expression, as translation also depends on the availability of essential metabolites, including metabolic energy sources, coenzymes, amino acids. Without adequate less efficient, potentially leading to higher dosing requirements or poorer therapeutic outcomes LNP therapies. To address this, we develop a metabolite co-delivery strategy by encapsulating metabolites within LNPs, hypothesizing that our approach can uniformly improve delivery. Instead adding fifth component organic phase, involves mixing with payload in aqueous while maintaining molar ratio components phase during formulation. We verify vitro vivo, highlighting broad applicability through mechanism efficacy studies across multiple cell lines, physiological conditions, such normoxia (i.e., 21% oxygen), hypoxia 1% mice. Taken collectively, anticipate serve generalizable enhance vivo expression using offering study treatment disease.

Language: Английский

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Customizable Polymeric Nanoparticle Materials Optimized on Hypoxic Cells Facilitate mRNA Expression in the Lungs In Vivo

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: May 27, 2025

Abstract mRNA therapy has shown great potential in treating lung diseases by enabling transient protein expression without permanently altering the genome. Despite advancements, most delivery systems, such as lipid nanoparticles and polymeric nanoparticles, predominantly express liver, limiting their effectiveness for extrahepatic organs like lungs. Furthermore, hypoxia, a common feature of many pulmonary diseases, significantly reduces translation synthesis, impacting therapeutic outcomes. In this study, we present Tunable Lung Expressing Nanoparticle Platform ( TULEP ) designed to enhance lungs improve under hypoxic conditions. Our approach involved combinatorial synthesis polymers with varied hydrocarbon tail lengths reaction equivalencies, followed formulation into mRNA‐loaded nanoparticles. These were characterized size, charge, encapsulation efficiency, mechanistic efficacy studies normoxia hypoxia performed vitro. vivo demonstrated that top‐performing s mRNA‐encoded well‐tolerated fashion suggested weight loss, blood paneling, histological analyses. Taken together, these results highlight viable platform tunable highlighting long‐term disease therapy.

Language: Английский

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Flow cytometric analysis of the murine placenta to evaluate nanoparticle platforms during pregnancy

Placenta, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

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A Chemoinformatic-Guided Synthesis of a Spleen-Expressing mRNA Lipid Nanoparticle Platform

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

mRNA lipid nanoparticles (LNPs) are a powerful technology that actively being investigated for their ability to prevent, treat, and study disease. However, major limitation remains: achieving extrahepatic expression. The development of new carriers could enable the expression in non-liver targets, thus expanding utility mRNA-based medicines. In this study, we use combination chemoinformatic-guided material synthesis design experiment optimization spleen-expressing nanoparticle (SE-LNP). We begin with novel cholesterol derivative followed by SE-LNP formulation experiment-guided identify three lead SE-LNPs. then evaluate

Language: Английский

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