Journal of the American Chemical Society, Год журнала: 2024, Номер 146(49), С. 34209 - 34220
Опубликована: Ноя. 25, 2024
Systemic mRNA delivery to specific cell types remains a great challenge. We herein report new class of crown-like biodegradable ionizable lipids (CBILs) for predictable lung-selective by leveraging the metal coordination chemistry. Each CBIL contains an impressive amino core that coordinates with various ions such as Zn
Язык: Английский
Journal of the American Chemical Society, Год журнала: 2024, Номер 146(22), С. 15085 - 15095
Опубликована: Май 22, 2024
The spleen emerges as a pivotal target for mRNA delivery, prompting continual quest specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate pronounced preference delivery into the with exceptional We optimized IMIL structures by constructing screening multidimensional library containing multiple heads, tails, linkers perform structure–activity correlation analysis. Following high-throughput in vivo screening, identified A3B7C2 top-performing spleen-specific via formulated LNPs, achieving remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent dendritic cell Comparative analyses revealed achieved notable 2.8-fold 12.9-fold increase compared SM102 DLin-MC3-DMA formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement expression SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues further research delivery. This work offers valuable insights swift discovery rational design candidates tailored transfection, thereby facilitating application therapeutics spleen-related interventions.
Язык: Английский
Процитировано
20
Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(5)
Опубликована: Янв. 30, 2025
The ionizable lipid component of nanoparticle (LNP) formulations is essential for mRNA delivery by facilitating endosomal escape. Conventionally, these lipids are synthesized through complex, multistep chemical processes that both time-consuming and require significant engineering. Furthermore, the development new hindered a limited understanding structure-activity relationships effective delivery. In this work, we have developed modular platform utilizing Passerini reaction to rapidly generate large, chemically diverse libraries biodegradable lipids. This high-throughput approach enables systematic exploration various components–head groups, tails, spacers–and their impacts on efficiency. By investigating hydrogen bonding potential between lipid’s head groups mRNA’s ribose phosphate found optimizing methylene units linkages could enhance escape and, consequently, efficiencies. Leveraging insight, our has led identification A4B4-S3, which outperforms current clinical benchmark, SM-102, in gene editing efficacy mouse liver following systemic administration demonstrates promise repeat-dose protein replacement treatments. work not only offers rapid, scalable method synthesis but also deepens relationships, paving way more therapeutics.
Язык: Английский
Процитировано
4
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
3
Journal of Controlled Release, Год журнала: 2024, Номер 372, С. 113 - 140
Опубликована: Июнь 15, 2024
Язык: Английский
Процитировано
15
Research, Год журнала: 2024, Номер 7
Опубликована: Янв. 1, 2024
Messenger RNA (mRNA) has emerged as an innovative therapeutic modality, offering promising avenues for the prevention and treatment of a variety diseases. The tremendous success mRNA vaccines in effectively combatting coronavirus disease 2019 (COVID-19) evidences unlimited medical potential technology. Overcoming challenges related to stability, immunogenicity, precision targeting been made possible by recent advancements lipid nanoparticles (LNPs). This review summarizes state-of-the-art LNP-mRNA-based therapeutics, including their structure, material compositions, design guidelines, screening principles. Additionally, we highlight current preclinical clinical trends LNP-mRNA therapeutics broad range treatments ophthalmological conditions, cancer immunotherapy, gene editing, rare-disease medicine. Particular attention is given translation evolution into broader spectrum therapeutics. We explore concerns aspects inadequate extrahepatic efficacy, elevated doses, safety concerns, large-scale production procedures. discussion may offer insights perspectives on near- long-term development prospects
Язык: Английский
Процитировано
12
Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 211, С. 115346 - 115346
Опубликована: Июнь 6, 2024
Язык: Английский
Процитировано
8
ACS Nano, Год журнала: 2024, Номер 18(17), С. 11335 - 11348
Опубликована: Апрель 15, 2024
Leveraging the extensive surface area of lungs for gene therapy, inhalation route offers distinct advantages delivery. Clinical nebulizers that employ vibrating mesh technology are standard choice converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage nanoparticles due shearing forces. Here, we introduce a microfluidic aerosolization platform (MAP) preserves structural and physicochemical integrity lipid nanoparticles, enabling safe efficient delivery respiratory system. Our results demonstrated superiority MAP over conventional nebulizer, as avoided problems such particle aggregation, loss encapsulation, deformation nanoparticle morphology. Notably, aerosolized generated by device led enhanced transfection efficiency across various cell lines. In vivo experiments with mice inhaled these revealed successful lung-specific without observable signs toxicity. This may represent an advancement pulmonary precise effective nanoparticles.
Язык: Английский
Процитировано
7
Small, Год журнала: 2024, Номер unknown
Опубликована: Май 13, 2024
Complete encapsulation of nucleic acids by lipid-based nanoparticles (LNPs) is often thought to be one the main prerequisites for successful acid delivery, as lipid environment protects mRNA from degradation external nucleases and assists in initiating delivery processes. However, via a preformed vesicle approach (PFV-LNPs) defies this precondition. Unlike traditional LNPs, PFV-LNPs are formed solvent-free mixing process, leading superficial localization. While demonstrating low efficiency RiboGreen assay, improved retina up 50% compared LNP analogs across several benchmark formulations, suggesting utility regardless composition. Successful gene editors' observed retinal pigment epithelium photoreceptors validated mice, non-human primates, human organoids. Deploying editing experiments result similar extent analogous (up 3% on genomic level) Ai9 reporter mouse model; but, remarkably, tolerability significantly PFV-LNP treatment. The study findings indicate that formulation process can greatly influence transfection outcomes, improving treatment safety without sacrificing efficacy.
Язык: Английский
Процитировано
7
Advanced Science, Год журнала: 2025, Номер unknown
Опубликована: Фев. 18, 2025
Abstract Targeted delivery of mRNA with lipid nanoparticles (LNPs) holds great potential for treating pulmonary diseases. However, the lack rational design principles efficient lung‐homing lipids hinders prevalence therapeutics in this organ. Herein, combinatorial screening structure‐function analysis is applied to rationalize strategy nonpermanently charged lung‐targeted ionizable lipids. It discovered that carrying N‐methyl and secondary amine groups heads, three tails originated from epoxyalkanes, exhibiting superior selectivity efficiency. Representative systematically variation chemical structures are selected study well‐known but still puzzling “protein corona” adsorbed on surface LNPs. In addition commonly used corona‐biomarker vitronectin, other arginine‐glycine‐aspartic acid (RGD)‐rich proteins usually involved collagen‐containing extracellular matrix, such as fibrinogen fibronectin have also been identified a strong correlation lung tropism. This work provides insight into lung‐targeting reveals previously unreported function RGD‐rich protein corona
Язык: Английский
Процитировано
1
Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(11)
Опубликована: Март 4, 2024
Due to its small size and lifelong optical transparency, the fish Danionella cerebrum is an emerging model organism in biomedical research. How can this vertebrate under 12 mm length produce sounds over 140 dB? We found that it possesses ...Motion basis of nearly all animal behavior. Evolution has led some extraordinary specializations propulsion mechanisms among invertebrates, including mandibles dracula ant claw pistol shrimp. In contrast, ...
Язык: Английский
Процитировано
6