Machine learning-assisted design of immunomodulatory lipid nanoparticles for delivery of mRNA to repolarize hyperactivated microglia DOI Creative Commons
Mehrnoosh Rafiei, Akbar Shojaei, Ying Chau

et al.

Drug Delivery, Journal Year: 2025, Volume and Issue: 32(1)

Published: March 3, 2025

Regulating inflammatory microglia presents a promising strategy for treating neurodegenerative and autoimmune disorders, yet effective therapeutic agents delivery to these cells remains challenge. This study investigates modified lipid nanoparticles (LNP) mRNA hyperactivated microglia, particularly those with pro-inflammatory characteristics, utilizing supervised machine learning (ML) classifiers. We developed screened library of 216 LNP formulations varying compositions, N/P ratios, hyaluronic acid (HA) modifications. The transfection efficiency eGFP was assessed in the BV-2 murine cell line under different immunological states, including resting activated conditions (LPS-activated IL4/IL13-activated). ML-guided morphometric analysis tracked phenotypes various subtypes before after transfection. Four ML classifiers were investigated predict phenotypic changes based on design parameters. Multi-Layer Perceptron (MLP) neural network emerged as best-performing model, achieving weighted F1-scores ≥0.8. While it accurately predicted responses from LPS-activated cells, struggled IL4/IL13-activated cells. MLP model validated by predicting performance four unseen delivering BV2 HA-LNP2 optimal formulation target IL10 mRNA, effectively suppressing phenotypes, evidenced shifts morphology, increased expression, reduced TNF-α levels. also evaluated human iPSC-derived confirming its efficacy modulating responses. highlights potential tailored techniques enhance therapy neuroinflammatory disorders leveraging carrier's immunogenic properties modulate microglial

Language: Английский

Aptamer-Based Targeted Protein Degradation DOI Creative Commons
Yuan Liu, Xu Qian,

Chunyan Ran

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(7), P. 6150 - 6164

Published: March 21, 2023

The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout abnormal proteins is inseparable from accurate identification within complex environments. Guided by these precepts, small molecules, antibodies, are commonly used as recognition tools for developing targeted degradation (TPD) technology. Indeed, TPD has shown tremendous prospects chronic diseases, rare cancer research, and other fields. Meanwhile, aptamers short RNA DNA oligonucleotides that can bind to target with high specificity strong affinity. Accordingly, actively designing constructing this perspective, we provide a brief introduction technology its current progress, summarize application challenges. Recent advances aptamer-based reviewed, together corresponding challenges outlooks.

Language: Английский

Citations

49
Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing DOI
Emily L. Han, Marshall S. Padilla, Rohan Palanki

et al.

Nano Letters, Journal Year: 2024, Volume and Issue: 24(5), P. 1477 - 1486

Published: Jan. 23, 2024

Lipid nanoparticle (LNP)-mediated nucleic acid therapies, including mRNA protein replacement and gene editing hold great potential in treating neurological disorders neurodegeneration, brain cancer, stroke. However, delivering LNPs across the blood-brain barrier (BBB) after systemic administration remains underexplored. In this work, we engineered a high-throughput screening transwell platform for BBB (HTS-BBB), specifically optimized LNPs. Unlike most assays, which only assess transport an endothelial monolayer, HTS-BBB simultaneously measures LNP transfection of cells themselves. We then use to screen library 14 made with structurally diverse ionizable lipids demonstrate it is predictive

Language: Английский

Citations

28
Breaking the mold with RNA—a “RNAissance” of life science DOI Creative Commons
Charles H. Jones,

John R. Androsavich,

N. So

et al.

npj Genomic Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 9, 2024

Abstract In the past decade, RNA therapeutics have gone from being a promising concept to one of most exciting frontiers in healthcare and pharmaceuticals. The field is now entering what many call renaissance or “RNAissance” which fueled by advances genetic engineering delivery systems take on more ambitious development efforts. However, this occurring at an unprecedented pace, will require different way thinking if live up its full potential. Recognizing need, article provide forward-looking perspective medical products potential long-term innovations policy shifts enabled revolutionary game-changing technological platform.

Language: Английский

Citations

17
Advanced Delivery Systems for Gene Editing: A Comprehensive Review from the GenE-HumDi COST Action Working group DOI Creative Commons
Alessia Cavazza, Francisco J Molina-Estévez, Álvaro Plaza Reyes

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2025, Volume and Issue: 36(1), P. 102457 - 102457

Published: Jan. 18, 2025

Language: Английский

Citations

2
The mRNA Vaccine Revolution: COVID-19 Has Launched the Future of Vaccinology DOI
Zhongfeng Ye, Joseph F. Harmon, Wei Ni

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(16), P. 15231 - 15253

Published: Aug. 3, 2023

During the COVID-19 pandemic, mRNA (mRNA) vaccines emerged as leading vaccine candidates in a record time. Nonreplicating (NRM) and self-amplifying (SAM) technologies have been developed into high-performing clinically viable against range of infectious agents, notably SARS-CoV-2. demonstrate efficient vivo delivery, long-lasting stability, nonexistent risk infection. The stability translational efficiency vitro transcription (IVT)-mRNA can be further increased by modulating its structural elements. In this review, we present comprehensive overview recent advances, key applications, future challenges field mRNA-based vaccinology.

Language: Английский

Citations

38
Bile acid-containing lipid nanoparticles enhance extrahepatic mRNA delivery DOI Creative Commons
Savan K. Patel, Margaret M. Billingsley,

Alvin J. Mukalel

et al.

Theranostics, Journal Year: 2023, Volume and Issue: 14(1), P. 1 - 16

Published: Oct. 30, 2023

Lipid nanoparticles (LNPs) have emerged as a viable, clinically-validated platform for the delivery of mRNA therapeutics. LNPs been utilized systems applications including vaccines, gene therapy, and cancer immunotherapy. However, LNPs, which are typically composed ionizable lipids, cholesterol, helper lipid-anchored polyethylene glycol, often traffic to liver limits therapeutic potential platform. Several approaches proposed resolve this tropism such post-synthesis surface modification or addition synthetic cationic lipids.

Language: Английский

Citations

24
Current status and trends in small nucleic acid drug development: Leading the future DOI Creative Commons
Yuxi Miao, Chen Fu, Zhaojin Yu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(9), P. 3802 - 3817

Published: May 13, 2024

Small nucleic acid drugs, composed of nucleotides, represent a novel class pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), interfering (siRNAs), microRNAs (miRNAs), aptamers. The emergence drugs as focal point in contemporary biopharmaceutical research is attributed to remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, prolonged activity. Overcoming challenges such poor stability, immunogenicity, permeability issues have been addressed through the integration chemical modifications drug delivery systems. This review provides an overview current status prospective trends development. Commencing with historical context, we introduce primary classifications mechanisms drugs. Subsequently, delve into advantages U.S. Food Drug Administration (FDA) approved mainly discuss encountered during Apart researching modification system efficiently deliver enrich tissues, promoting endosomal escape critical scientific question important direction siRNA Future directions field will prioritize addressing these facilitate clinical transformation

Language: Английский

Citations

16
Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism DOI Creative Commons
Mahboubeh Hosseini-Kharat, Kristen E. Bremmell, Clive A. Prestidge

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2025, Volume and Issue: 33(1), P. 101436 - 101436

Published: Feb. 16, 2025

Lipid nanoparticles (LNPs) are now highly effective transporters of nucleic acids to the liver. This liver-specificity is largely due their association with certain serum proteins, most notably apolipoprotein E (ApoE), which directs them liver cells by binding low-density lipoprotein (LDL) receptors on hepatocytes. The liver's distinct anatomy, its various specialized cell types, also influences how LNPs taken up from circulation, cleared, and they in delivering treatments. In this review, we consider factors that facilitate LNP's targeting explore latest advances liver-targeted LNP technologies. Understanding targeted can help for design optimization nanoparticle-based therapies. Comprehension cellular interaction biodistribution not only leads better treatments diseases but delivers insight directing other tissues, potentially broadening range therapeutic applications.

Language: Английский

Citations

1
Dual targeted lipid nanoparticles for enhanced DNA delivery and transfection of breast cancer cells DOI Creative Commons
Claudia Lotter,

Megan Anna Stierli,

Ramya Deepthi Puligilla

et al.

European Journal of Pharmaceutics and Biopharmaceutics, Journal Year: 2025, Volume and Issue: 209, P. 114674 - 114674

Published: Feb. 21, 2025

Language: Английский

Citations

1
Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy DOI
Kelly Godbout, Jacques P. Tremblay

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(10), P. 2129 - 2129

Published: Oct. 7, 2022

Gene therapy holds great promise in the treatment of genetic diseases. It is now possible to make DNA modifications using CRISPR system. However, a major problem remains: delivery these CRISPR-derived technologies specific organs. Lipid nanoparticles (LNPs) have emerged as very promising method. when delivering LNPs intravenously, most cargo trapped by liver. Alternatively, injecting them directly into organs, such brain, requires more invasive procedures. Therefore, developing crucial for their future clinical use. Modifying composition lipids allows deliveries some In this review, we identified effective compositions and proportions target lungs, muscles, heart, liver, spleen, bones.

Language: Английский

Citations

31