Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 370, P. 614 - 625
Published: May 14, 2024
Language: Английский
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
Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 207, P. 115194 - 115194
Published: Feb. 10, 2024
Language: Английский
Citations
9
Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 370, P. 379 - 391
Published: May 4, 2024
Although various types of mRNA-based vaccines have been explored, the optimal conditions for induction both humoral and cellular immunity remain rather unknown. In this study, mRNA nucleoside-modified in lipoplexes (LPXs) or lipid nanoparticles (LNPs) were evaluated after administration mice through different routes, assessing delivery, tolerability immunogenicity. addition, we investigated whether could benefit from inclusion adjuvant alpha-galactosylceramide (αGC), an invariant Natural Killer T (iNKT) cell ligand. Intramuscular (IM) vaccination with ovalbumin (OVA)-encoding encapsulated LNPs adjuvanted αGC showed highest antibody- CD8+ responses. Furthermore, observed that addition signal peptides endocytic sorting signals either LAMP1 HLA-B7 OVA-encoding sequence further enhanced activation although reducing IgG antibody Moreover, ionizable lipidoid C12–200 exhibited higher pro-inflammatory- reactogenic activity compared to SM-102, correlating increased antitumor potential. We also enhance clinically relevant LNP vaccines, thereby promoting therapeutic Finally, a Listeria monocytogenes vaccine supplemented synergistic protective effects against listeriosis, highlighting key advantage co-activating iNKT cells antibacterial vaccines. Taken together, our study offers multiple insights optimizing design disease applications, such as cancer intracellular bacterial infections.
Language: Английский
Citations
9
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: Jan. 24, 2025
Language: Английский
Citations
1
Advanced Science, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 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
Language: Английский
Citations
1
Nano Letters, Journal Year: 2024, Volume and Issue: 24(26), P. 8080 - 8088
Published: June 18, 2024
Among various mRNA carrier systems, lipid nanoparticles (LNPs) stand out as the most clinically advanced. While current clinical trials of mRNA/LNP therapeutics mainly address liver diseases, potential therapy extends far beyond─yet to be unraveled. To fully unlock promises therapy, there is an urgent need develop safe and effective LNP systems that can target extrahepatic organs. Here, we report on development sulfonium (sLNPs) for systemic delivery lungs. sLNP effectively specifically delivered lungs following intravenous administration in mice. No evidence lung inflammation or toxicity major organs was induced by sLNP. Our findings demonstrated newly developed lung-specific platform both efficacious. It holds great promise advancing new mRNA-based therapies treatment lung-associated diseases conditions.
Language: Английский
Citations
7
ACS Nano, Journal Year: 2024, Volume and Issue: 18(35), P. 24204 - 24218
Published: Aug. 22, 2024
The delivery of mRNA into the lungs is key to solving infectious and intractable diseases that frequently occur in lungs. Since inhalation using a nebulizer most promising method for lungs, there have been many attempts toward adapting lipid nanoparticles inhalation. However, conventional nanoparticles, which shown great effectiveness systemic intramuscular vaccination, are not effective pulmonary due their structural instability during nebulization inability adapt microenvironment. To address these issues, we developed an ionizable liposome-mRNA lipocomplex (iLPX). iLPX has highly ordered bilayer structure, increases stability nebulization, its poly(ethylene glycol)-free composition allows it infiltrate low serum environment surfactant layer We selected inhalation-optimized (IH-iLPX) multistep screening procedure mimics process inhaled nanoparticles. IH-iLPX showed higher transfection efficiency compared after with no observed toxicity
Language: Английский
Citations
4
Biomacromolecules, Journal Year: 2025, Volume and Issue: 26(1), P. 623 - 634
Published: Jan. 2, 2025
mRNA-based therapies hold tremendous promise for treating various diseases, yet their clinical success is hindered by delivery challenges. This study developed a library of 140 lipocationic Poly(β-amino ester)s (PBAEs) and formulated lipid-polymer hybrid nanoparticles (LPHs) with four helper lipids, including 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), to enhance mRNA delivery. Initial in vitro screening representative PBAEs identified the D/P4-1 formulation (DOTAP/PBAE molar ratio 4:1) as most effective. Further using this eight top-performing LPHs. In vivo experiments confirmed high luciferase expression spleen lungs mice following intravenous administration Luc mRNA-loaded Detailed analysis revealed that DOTAP incorporation influenced LPH properties, apparent pKa, surface charge, internal hydrophobicity, enabling enhanced release cellular uptake. demonstrates potent approaches modulate PBAE-lipid nanoparticle properties altering PBAE structures composition, offering insights designing effective carriers therapeutics.
Language: Английский
Citations
0
ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 13, 2025
Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential precise therapeutic outcomes and minimized side effects various disease models. However, achieving targeted beyond the liver a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto head cholesterol-like structure incorporated them as fifth component into conventional commercial LNPs ALC-0315 SM-102. Selective targeting achieved adjusting proportion LNP. Specifically, spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% efficiency, while lung-targeted 102-Sito-40% up 78%. Moreover, when strategy applied self-developed lipid named U-101 instead SM-102, efficiencies spleen lungs reach 96 71%, respectively. Multiple assessments suggest that inclusion does not compromise stability, indicated consistent particle size, polydispersity index (PDI), encapsulation efficiency. Furthermore, test results kidney function immunogenicity reveal no increase toxicity vivo following introduction component. Additional studies vitro cytotoxicity, lysosomal escape, cellular transfection efficiency confirm diminish performance. Taken together, incorporation leads delivery, which features strong organ selectivity, high safety, suitability further evaluation.
Language: Английский
Citations
0
Nano Letters, Journal Year: 2025, Volume and Issue: unknown
Published: March 14, 2025
It is well established that the physicochemical properties of lipid nanoparticles (LNPs) can govern their interactions with various biological barriers. One property hypothesized to influence nanoparticle-cell elasticity. Here, we formulate LNPs naturally occurring cholesterol analogs tune LNP elasticity and study its role on mRNA delivery placenta. was measured via atomic force microscopy where these exhibited Young's moduli ranging from 71.0 ± 26.2 411.4 145.7 kPa. In vitro screening in placental trophoblasts showed stiffer improved uptake compared softer LNPs. Following intravenous administration pregnant mice, incorporating β-sitosterol enhanced reduced liver containing only cholesterol. These results demonstrate ability promote highlight potential tuning improve LNP-mediated organs interest.
Language: Английский
Citations
0