Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(4)

Published: Aug. 7, 2023

Abstract Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent degradation of cargo during blood circulation. Upon entry into cell, specific components lipid can promote endosomal escape acids. These basic properties as acid carriers. As exhibit hepatic aggregation characteristics, enhancing targeting out liver is a crucial way to improve administrated in vivo. Meanwhile, loaded often considered inadequate, and therefore, much effort devoted intracellular release efficiency Here, different strategies efficiently deliver from concluded their mechanisms investigated. In addition, based on information that trials or have completed trials, issues necessary be approached translation discussed, which it hoped will shed light development LNP drugs.

Language: Английский

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Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery

Advanced Materials, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 4, 2023

Abstract Lipid‐based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, NAD delivery efficiency and safety still unsatisfactory, which are, to a large extent, due existence of multi‐level physiological barriers in vivo. It is important elucidate interactions between these LBNPs, will guide more rational design efficient with low adverse effects facilitate broader therapeutics. This review describes obstacles challenges biological at systemic, organ, sub‐organ, cellular, subcellular levels. The strategies overcome comprehensively reviewed, mainly including physically/chemically engineering LBNPs directly modifying by auxiliary treatments. Then potentials successful translation preclinical studies into clinic discussed. In end, forward look on manipulating protein corona (PC) addressed, may pull off trick overcoming those significantly improve efficacy LBNP‐based NADs

Language: Английский

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The Evolving Landscape of NF Gene Therapy: Hurdles and Opportunities

Molecular Therapy — Nucleic Acids, Journal Year: 2025, Volume and Issue: 36(1), P. 102475 - 102475

Published: Feb. 4, 2025

Neurofibromatosis type 1 (NF1)- and NF2-related schwannomatosis are rare autosomal dominant monogenic disorders characterized by a predisposition for nerve-associated tumors. Current treatments focus on symptomatic management, but advancements in the gene therapy field present unique opportunities to treat genetic underpinnings develop curative therapies NF. Approaches such as nonsense suppression agents oligonucleotide becoming more mature have emerging preclinical data context of Furthermore, there has been progress developing vectors that can be delivered locally into tumors ablate or shrink their size. While still nascent research area, addition repair strategies hold tremendous promise prevention treatment NF-related These technologies will also require parallel development delivery able target Schwann cells from which most commonly arise. This review seeks contextualize these hurdles remain clinical adoption.

Language: Английский

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Biofluid specific protein coronas affect lipid nanoparticle behavior in vitro

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 373, P. 481 - 492

Published: July 25, 2024

Lipid nanoparticles (LNPs) have successfully entered the clinic for delivery of mRNA- and siRNA-based therapeutics, most recently as vaccines COVID-19. Nevertheless, there is a lack understanding regarding their in vivo behavior, particular cell targeting. Part this LNP tropism based on adherence endogenous protein to particle surface. This forms so-called corona that can change, amongst other things, circulation time, biodistribution cellular uptake these particles. The formation corona, turn, dependent nanoparticle properties (e.g., size, charge, surface chemistry hydrophobicity) well biological environment from which it derived. With potential gene therapy target virtually any disease, administration sites than intravenous route are considered, resulting tissue specific coronas. For neurological diseases, intracranial LNPs results cerebral spinal fluid derived possibly changing lipid compared administration. Here, differences between plasma CSF coronas clinically relevant formulation were studied vitro. Protein analysis showed incubated human (C-LNPs) developed composition differed (P-LNPs). Lipoproteins whole, but apolipoprotein E, represented higher percentage total C-LNPs P-LNPs. resulted improved P-LNPs, regardless origin. Importantly, did not directly translate into more efficient cargo delivery, underlining further assessment such mechanisms necessary. These findings show biofluid alter functionality, suggesting site could affect efficacy needs be considered during development formulation.

Language: Английский

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The piper at the gates of brain: A systematic review of surface modification strategies on lipid nanoparticles to overcome the Blood-Brain-Barrier

International Journal of Pharmaceutics, Journal Year: 2024, Volume and Issue: unknown, P. 124686 - 124686

Published: Sept. 1, 2024

The Blood-Brain Barrier (BBB) significantly impedes drug delivery to the central nervous system. Nanotechnology, especially surface-functionalized lipid nanoparticles, offers innovative approaches overcome this barrier. However, choosing an effective functionalization strategy is challenging due lack of detailed comparative analysis in current literature. Our systematic review examined various strategies and their impact on BBB permeability from 2041 identified articles, which 80 were included for data extraction. Peptides most common modification (18) followed by mixed (12) proteins (9), antibodies (7), other (8). Interestingly, 26 studies showed penetration with unmodified or modified nanoparticles using commonly applied such as PEGylation surfactant addition. Statistical across 42 correlation between higher vivo permeation improvements nanoparticle type, size, category. highest ratios found nanostructured carriers biomimetic systems, particle sizes under 150 nm, those applying strategies. interstudy heterogeneity we observed highlights importance adopting standardized evaluation protocols enhance comparability. aims provide a insight identify future research directions development more systems brain help improve treatment neurological psychiatric disorders tumours.

Language: Английский

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EPHA2 and scavenger receptor-directed trafficking enhances endosomal leakiness and antisense therapy delivery

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Summary The potential for using therapeutic antisense oligonucleotides (ASOs) has been hampered by lack of understanding how they enter cells and subsequently access their targets. Endocytosis contributes to ASO uptake, but the machinery mediating subsequent trafficking permit suppression target mRNAs not described. Here, we show that engagement with a scavenger receptor (CD44) activates ERK-RSK axis promote serine phosphorylation tyrosine kinase (EPHA2). Serine EPHA2 permits endocytosis, trafficking, accumulation ASOs in nuclear-adjacent endosomes. These endosomes then become leaky, allowing escape effectively suppress mRNA expression. Inhibition stress granule-mediated repair leaky further enhances effectiveness. data identify an endocytic route nucleus which may be exploited maximise effectiveness ASO-mediated therapies.

Language: Английский

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Unveiling Pharmacogenomics Insights into Circular RNAs: Toward Precision Medicine in Cancer Therapy

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 535 - 535

Published: April 5, 2025

Pharmacogenomics is revolutionizing precision medicine by enabling tailored therapeutic strategies based on an individual genetic and molecular profile. Circular RNAs (circRNAs), a distinct subclass of endogenous non-coding RNAs, have recently emerged as key regulators drug resistance, tumor progression, responses. Their covalently closed circular structure provides exceptional stability resistance to exonuclease degradation, positioning them reliable biomarkers novel targets in cancer management. This review comprehensive analysis the interplay between circRNAs pharmacogenomics, focusing their role modulating metabolism, efficacy, toxicity profiles. We examine how circRNA-mediated regulatory networks influence chemotherapy alter targeted therapy responses, impact immunotherapy outcomes. Additionally, we discuss emerging experimental tools bioinformatics techniques for studying circRNAs, including multi-omics integration, machine learning-driven biomarker discovery, high-throughput sequencing technologies. Beyond diagnostic potential, are being actively explored agents delivery vehicles. Recent advancements circRNA-based vaccines, engineered CAR-T cells, synthetic circRNA therapeutics highlight transformative potential oncology. Furthermore, address challenges standardization, reproducibility, clinical translation, emphasizing need rigorous validation frameworks facilitate integration into practice. By incorporating profiling pharmacogenomic strategies, this underscores paradigm shift toward highly personalized therapies. hold immense overcome enhance treatment optimize patient outcomes, marking significant advancement

Language: Английский

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Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 24, 2025

Abstract Background Dysregulation of microRNA (miRNA) expression in the brain is a common feature neurodegenerative diseases. Beyond their conventional role regulating gene at post-transcriptional level, certain miRNAs can act extracellularly as signaling molecules. Our study elucidates identity such miRNA species serving ligands for membrane receptors expressed central nervous system (CNS) neurons and impact on context disease. Methods We combined machine learning approach with analysis disease-associated databases to predict Alzheimer’s disease (AD)-associated potential molecules single-stranded RNA-sensing Toll-like (TLRs) 7 8. TLR-expressing HEK-Blue reporter cells, primary murine microglia, human THP-1 macrophages were used validate AD mouse TLR7 and/or TLR8. Interaction between cortical applied was analyzed by live cell imaging confocal microscopy. Transcriptome changes exposed assessed RNAseq RT-qPCR. The extracellular miRNAs’ effects CNS neuron structure investigated cultures iPSC-derived immunocytochemistry. employed model intrathecal injection assess acting vivo. Results identified AD-associated miR-124-5p, miR-92a-1-5p, miR-9-5p, miR-501-3p novel endogenous These being stable active taken up via endocytosis induced neuronal inflammation-, proliferation-, apoptosis-related expression. Exposure both led alterations dendrite axon structure, synapse protein expression, viability sequence-dependent fashion. Extracellular introduction into cerebrospinal fluid mice resulted synapses, loss cerebral cortex. Most observed miRNA-induced involved TLR7/8 signaling. Conclusion Neurodegenerative form including neurons, thereby modulating viability.

Language: Английский

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Nanoparticle organelle targeting kinetics: a discussion on application

Journal of Drug Delivery Science and Technology, Journal Year: 2025, Volume and Issue: unknown, P. 107028 - 107028

Published: May 1, 2025

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Engineered multi-domain lipid nanoparticles for targeted delivery

Chemical Society Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

This review introduces a four-domain framework to dissect engineered lipid nanoparticles (LNPs) rationally and explores their programmability, in vivo behavior, emerging AI-driven strategies for design, simulation, clinical translation.

Language: Английский

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