Advanced Drug Delivery Reviews, Год журнала: 2024, Номер unknown, С. 115460 - 115460
Опубликована: Окт. 1, 2024
Язык: Английский
Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(1), С. 102457 - 102457
Опубликована: Янв. 18, 2025
Язык: Английский
Процитировано
2
Advanced Science, Год журнала: 2025, Номер unknown
Опубликована: Фев. 8, 2025
Nanoparticle-based mRNA delivery offers a versatile platform for innovative therapies. However, most of the current systems are limited by poor serum tolerance, suboptimal endosomal escape and efficacy. Herein, highly efficient mRNA-delivering material is identified from library fluoropolymers. The lead FD17 shows exceptional stability escape, enabling into various cell types, surpassing commercial reagents such as Lipofectamine 3000. formed nanoparticles adsorb abundant albumin on surface, which facilitates cellular uptake via scavenger receptor-mediated endocytosis. enables mRNAs encoding CRE, Cas9, base editor hyCBE genome editing. mediates CRISPR/Cas9 gene therapy intraocular injection effectively down-regulates vascular endothelial growth factor A in retinal pigment epithelial cells mice, yielding promising therapeutic responses against laser-induced choroidal neovascularization. discovered this study great promise development therapeutics to combat wide range diseases.
Язык: Английский
Процитировано
1
Cells, Год журнала: 2025, Номер 14(4), С. 277 - 277
Опубликована: Фев. 13, 2025
Prime editing is a genome technique that allows precise modifications of cellular DNA without relying on donor templates. Recently, several different prime editor proteins have been published in the literature, single- or double-strand breaks. When occurs, undergoes one repair pathways, and these processes can be modulated with use inhibitors. Firstly, this review provides an overview mechanisms their modulation by known In addition, we summarize editors provide comprehensive associated mechanisms. Finally, discuss delivery safety aspects editing.
Язык: Английский
Процитировано
1
ACS Nano, Год журнала: 2025, Номер unknown
Опубликована: Фев. 17, 2025
Messenger RNA (mRNA) encoding base editors, along with single guide RNAs (sgRNAs), have emerged as a promising therapeutic approach for various disorders. However, there is still insufficient exploration in achieving targeted and efficient delivery of mRNA sgRNA to multiple organs while ensuring high biocompatibility stability vivo. To address this challenge, we synthesized library 108 poly(β-amino) esters (PBAEs) by incorporating 100% hydrophobic side chains end-caps varying amines. These PBAEs were further formulated other excipients, including helper lipids, cholesterol, PEGylated form polymer–lipid nanoparticles (PLNPs). Structure–function analysis revealed that eLog P could serve predictive parameter determining the liver or lung tropism PLNPs. The end-capped monoamines was significantly higher compared those diamines. Leveraging these findings, expanded PBAE identified leading (7C8C8) efficiency outperforming current FDA-approved ionizable lipids (ALC-0315, SM-102, Dlin-MC3-DMA). LD50 empty PLNPs determined be 403.8 ± 49.46 mg/kg, indicating safety profile. Additionally, demonstrated sustained transfection activity at least 2 months when stored −20 °C after freezing 4 following lyophilization. Subsequently, vivo editing using achieved an impressive approximately 70% significant reduction protein levels exceeding 90%. Notably, synergistic effects observed through simultaneous disruption proprotein convertase subtilisin/kexin type 9 angiopoietin-like 3 genes, resulting low-density lipoprotein cholesterol over 60% several months. compelling findings provide strong support development platforms mRNA-based therapies.
Язык: Английский
Процитировано
1
ChemMedChem, Год журнала: 2025, Номер unknown
Опубликована: Фев. 17, 2025
Abstract Lipid nanoparticles (LNPs) have emerged as a transformative platform for the targeted delivery of therapeutic agents, revolutionizing treatment paradigms across spectrum diseases. Since inception liposomes in 1960s, lipid‐based nanotechnology has evolved to address limitations such poor bioavailability, off‐target effects, and instability, thereby enhancing efficacy safety drug administration. This review highlights latest advancements LNPs technology, focusing on their application cancer therapy, gene infectious disease management, glaucoma, other clinical areas. Recent studies underscore potential deliver messenger RNA (mRNA) small interfering (siRNA) precise genetic intervention, exemplified by breakthroughs interference CRISPR‐Cas9 genome editing. Additionally, been successfully employed ameliorate conditions, demonstrating versatility addressing both acute chronic disorders. However, challenges persist concerning large‐scale manufacturing, long‐term stability, comprehensive evaluations. Future research must focus optimizing formulations, exploring synergistic combinations with existing therapies, expanding scope treatable The integration into personalized medicine exploration applications diseases represent promising avenues further investigation. are poised play an increasingly central role development next‐generation therapeutics.
Язык: Английский
Процитировано
1
Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)
Опубликована: Ноя. 14, 2024
Abstract In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge can be largely attributed to demonstration of distinct advantages offered by various mRNA molecules, alongside rapid advancements nucleic delivery systems. It is noteworthy that immunogenicity presents a double-edged sword. context immunotherapy, extra supplementation adjuvant generally required for induction robust immune responses. Conversely, non-immunotherapeutic scenarios, activation unwanted considering host tolerability high expression demand mRNA-encoded functional proteins. Herein, mainly focused on linear non-replicating mRNA, we overview preclinical clinical progress prospects medicines encompassing vaccines other therapeutics. We also highlight importance focusing host-specific variations, including age, gender, pathological condition, concurrent medication individual patient, maximized efficacy safety upon administration. Furthermore, deliberate potential challenges may encounter realm disease treatment, current endeavors improvement, as well application future advancements. Overall, this review aims present comprehensive understanding mRNA-based therapies while illuminating prospective development drugs.
Язык: Английский
Процитировано
6
Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)
Опубликована: Дек. 20, 2024
Abstract CRISPR-based gene editing technology theoretically allows for precise manipulation of any genetic target within living cells, achieving the desired sequence modifications. This revolutionary advancement has fundamentally transformed field biomedicine, offering immense clinical potential treating and correcting disorders. In treatment most diseases, genome that avoids generation mixed byproducts is considered ideal approach. article reviews current progress base editors prime editors, elaborating on specific examples their applications in therapeutic field, highlights opportunities improvement. Furthermore, we discuss performance these technologies terms safety efficacy applications, analyze latest advancements directions could influence future development technologies. Our goal to outline relevance this rapidly evolving scientific preview a roadmap successful DNA therapies hereditary or idiopathic diseases.
Язык: Английский
Процитировано
5
Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113641 - 113641
Опубликована: Март 1, 2025
Язык: Английский
Процитировано
0
Опубликована: Апрель 16, 2025
Summary Many targeted therapies indirectly suppress cancer cells by inhibiting oncogenic signaling pathways such as Ras 1–4 . This renders them susceptible to resistance and limits their long-term clinical efficacy 4–10 Engineered protein circuits 11–25 have been envisioned an alternative pharmacological inhibition that directly rewires activity cell death. However, it has remained unclear whether engineered can potently safely treat cancers. Here, we show Ras-targeting accurately discriminate between non-cancer cells, circumvent intrinsic acquired mechanisms limit inhibitors, in vivo These combine three modules: a protease-based sensor responds broad spectrum of clinically relevant mutations, optional protease amplifier, protease-triggered death effectors. effectors flexibly trigger either non-inflammatory apoptosis or immunogenic pyroptosis, which shown extend therapeutic effects beyond transfected 26,27 The resulting sense-kill be safely, efficiently, transiently delivered mRNA lipid nanoparticles (LNPs). exhibited potent against Ras-mutant human lines with minimal off-target killing wild-type cells. In immunocompetent mice bearing aggressive, multifocal Ras-driven liver tumors, systemically-delivered mRNA-LNP significantly reduced tumor burden. Further, provided more than the inhibitors Sotorasib RMC-7977 7,28–30 , increased sensitivity Sotorasib-resistant vitro results establish potent, specific, programmable mechanism for treating other diseases.
Язык: Английский
Процитировано
0
Pharmaceutics, Год журнала: 2024, Номер 16(7), С. 918 - 918
Опубликована: Июль 10, 2024
Drug development costs can be significantly reduced if proven “platform” technologies are allowed to used without having validate their use. The most recent US Food and Administration (FDA) guideline brings more clarity, as well a greater focus on the complex that now for faster drug development. FDA has highlights use of lipid nanoparticles (LNPs) package deliver mRNA vaccines, gene therapy, short (2–20 length) synthetic nucleotides (siRNA). Additionally, monoclonal antibody cell is targeted. provides systematic process requesting platform status benefit from its advantages. It advanced science rationality into regulatory steps FDA’s approval drugs biologicals.
Язык: Английский
Процитировано
3