Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism

Molecular Therapy — Methods & Clinical Development, Год журнала: 2025, Номер 33(1), С. 101436 - 101436

Опубликована: Фев. 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.

Язык: Английский

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Construction of Chitosan Oligosaccharide-Coated Nanostructured Lipid Carriers for the Sustained Release of Strontium Ranelate

Tissue Engineering and Regenerative Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 12, 2025

Язык: Английский

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Development of a messenger RNA vaccine using pH-responsive dipeptide-conjugated lipids exhibiting reduced inflammatory properties

International Journal of Pharmaceutics, Год журнала: 2025, Номер unknown, С. 125485 - 125485

Опубликована: Март 1, 2025

Язык: Английский

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Mechanistic Intracellular Pharmacokinetic/Pharmacodynamic Modeling to Inform Development Strategies for Small Interfering RNA Therapeutics

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(2), С. 102516 - 102516

Опубликована: Март 17, 2025

Small interfering RNA (siRNA) therapeutics provide a targeted approach to silence disease-related genes, with notable success in liver-targeting applications. However, the quantitative effects of siRNA properties, such as stability and affinity, well biological factors like cell proliferation, mRNA turnover, abundance, on gene silencing, particularly for extrahepatic targets, remain poorly understood. To identify determinants influencing knockdown extent duration, we developed mechanistic intracellular pharmacokinetic/pharmacodynamic (PK/PD) model RNAiMAX-delivered siRNA, based cytoplasmic disposition, RISC-loaded exposure, across different targets MCF7 BT474 cells. The highlighted critical roles proliferation silencing duration turnover rates extent. In rapid-dividing cells, half-life drives profiles, whereas chemical stabilization extends slow-dividing Targets extremely low or high abundance pose challenges. While sufficient RISC occupancy is essential, increasing exposure has minimal impact extent; enhancing siRNA-mRNA target engagement more effective. also defined relationship maximal knockdown, governed by half-life, RISC-mediated cleavage rates. This PK/PD modeling provides insights into optimizing design selection therapeutic development.

Язык: Английский

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Influence of salt solution on the physicochemical properties and in vitro/ in vivo expression of mRNA/LNP

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 19, 2025

Lipid nanoparticles (LNPs) have revolutionized nucleic acid delivery, enabling significant advances in mRNA-based therapeutics. While extensive research has focused on lipid composition, the impact of preparation solutions LNP performance remains underexplored. This study systematically investigated effects pH, salt type, and concentration across key solutions—mRNA aqueous, dilution, exchange, storage solutions—on physicochemical properties, stability, expression efficiency SM102-based mRNA/LNPs. Findings revealed that pH mRNA aqueous solution was critical, with a 4 optimizing encapsulation (EE) cellular expression. The exchange solution's significantly influenced biodistribution, particularly liver-specific following intravenous intramuscular administration. Sucrose identified as essential for freeze-thaw 300 mM minimizing aggregation leakage. Furthermore, were shown to influence structural integrity LNPs, impacting their vivo vitro performance. These insights highlight importance conditions formulations clinical applications, offering foundation enhanced therapeutic design delivery.

Язык: Английский

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Exploring the Challenges of Lipid Nanoparticle Development: The In Vitro–In Vivo Correlation Gap

Vaccines, Год журнала: 2025, Номер 13(4), С. 339 - 339

Опубликована: Март 21, 2025

Background/Objectives: The development of lipid nanoparticles (LNPs) as delivery platforms for nucleic acids has revolutionised possibilities both therapeutic and vaccine applications. However, emerging studies highlight challenges in achieving reliable vitro–in vivo correlation (IVIVC), which delays the translation experimental findings into clinical This study investigates these potential discrepancies by evaluating physicochemical properties, vitro efficacy (across three commonly used cell lines), performance (mRNA expression efficacy) four LNP formulations. Methods: LNPs composed DSPC, cholesterol, a PEGylated lipid, one ionizable lipids (SM-102, ALC-0315, MC3, or C12-200) were manufactured using microfluidics. Results: All formulations exhibited comparable expected (size 70–100 nm, low PDI, near-neutral zeta potential, high mRNA encapsulation). In demonstrated variable LNP-mediated immortalised immune cells, with SM-102 inducing significantly higher protein (p < 0.05) than other cells. results revealed that ALC-0315 SM-102-based achieved without significant difference between them, while MC3- C12-200-based lower levels. As formulations, all elicited strong responses no differences among them. Conclusions: These complexities correlating outcomes demonstrate importance holistic evaluation strategies to optimise their translation.

Язык: Английский

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A Polysorbate-Based Lipid Nanoparticle Vaccine Formulation Induces In Vivo Immune Response Against SARS-CoV-2

Pharmaceutics, Год журнала: 2025, Номер 17(4), С. 441 - 441

Опубликована: Март 29, 2025

Background: Lipid nanoparticles (LNPs) have proven effective in delivering RNA-based modalities. Rapid approval of the COVID-19 vaccines highlights promise LNPs as a delivery platform for nucleic acid-based therapies and vaccines. Nevertheless, improved LNP designs are needed to advance next-generation other gene toward greater clinical success. components formulation excipients play central role biodistribution, immunogenicity, stability. Therefore, it is important understand, identify, assess appropriate lipid developing safe formulation. Herein, this study focused on novel Polysorbate-80 (PS-80)-based LNP. We hypothesized that substituting conventional linear PEG-lipids with PS-80, widely used, biocompatible injectable surfactant featuring branched PEG-like structure, may change biodistribution pattern enhance long-term By leveraging PS-80’s unique structural properties, aimed develop an mRNA-LNP extrahepatic robust freeze/thaw tolerance. Methods: employed stepwise optimization establish both composition buffer yield stable, high-performing PS-80-based SARS-CoV-2 (SC2-PS80 LNP). compared phosphate- versus tris-based buffers stability, examined multiple ratios, evaluated impact incorporating PS-80 (a PEG-lipid) vivo biodistribution. Various analytical assays were performed particle size, encapsulation efficiency, mRNA purity, vitro potency developed humanized mouse model was used measure its immunogenicity over six months storage at −80 °C. Results: Replacing standard 1,2-dimyristoyl-rac-glycero-3-methoxy polyethylene glycol-2000 (PEG-DMG) increased spleen-specific expression mRNA-LNPs after intramuscular injection. Formulating tris-sucrose-salt (TSS) preserved LNP’s physicochemical properties °C, whereas PBS-sucrose (PSS) less protective under frozen conditions. Notably, TSS-based SC2-PS80 elicited potent humoral immunity mice, including high anti-spike IgG titers pseudovirus neutralization, comparable freshly prepared formulations. Conclusions: A formulated TSS confers delivery, strong against following months. These findings offer promising pathway design therapeutics enhanced stability potential.

Язык: Английский

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Microfluidic Optimization of PEI-Lipid Hybrid Nanoparticles for Efficient DNA Delivery and Transgene Expression

Pharmaceutics, Год журнала: 2025, Номер 17(4), С. 454 - 454

Опубликована: Апрель 1, 2025

Background: Lipid nanoparticles (LNPs) and polyethyleneimine (PEI) have independently been used for DNA complexation delivery. However, non-ideal gene delivery efficiency toxicity hindered their clinical translation. We developed DNA-PEI-LNPs as a strategy to overcome these limitations enhance transgene expression. Methods: Three microfluidic mixing protocols were evaluated: (i) LNPs without PEI, (ii) single-step process incorporating PEI in the organic phase, (iii) two-step with pre-complexed before LNP incorporation. The influence of DNA/PEI ratios (1:1, 1:2, 1:3) DNA/lipid (1:10, 1:40) on particle properties was examined. Results: In luciferase formulations, higher (1:40) produced smaller particles (136 nm vs. 188 nm) improved cellular uptake (77% 50%). method transfection efficiency, LNP-Luc/PEI 1:3 (40) achieving ~1.9 × 106 relative light units (RLU) green fluorescent protein (GFP) studies, LNP-GFP/PEI showed ~23.8% GFP-positive cells, nearly twofold than LNP-GFP at ~12.6%. Conclusions: These results demonstrate capability microfluidic-prepared improve expression through optimized formulation strategies selection appropriate preparation methods.

Язык: Английский

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Nanomedicine constructed with plant-derived aromatic aldehydes treats low back pain by reversing the progression of lumbar facet joint osteoarthritis

Chemical Engineering Journal, Год журнала: 2025, Номер unknown, С. 162445 - 162445

Опубликована: Апрель 1, 2025

Язык: Английский

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Opportunities in Therapeutic mRNA Stabilization: Sequence, Structure, Adjuvants and Vectors

Advanced Therapeutics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

Abstract The reliance of current COVID‐19 mRNA lipid nanoparticles on cold storage increases the cost and reduces access to vaccines. As therapeutic expands other clinical opportunities, better methods stabilize medicines during shipping, storage, delivery are needed. This work reviews advances in design with a focus codon optimization, chemical modifications, RNA structures. Additionally, technologies promoting nanoparticle stabilization including ionizable lipids, excipients, lyophilization, inorganic systems reviewed. Application emerging improve may produce stable, “off‐the‐shelf” therapeutics that can be accessed worldwide.

Язык: Английский

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