DRUG METABOLISM AND DISPOSITION
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2026
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IF 3.6
Bo Sun,Zihui Jin,Xinwei Li,Xia Xiao,Zhenwei Jiang,Wei Xie,Leshuai Zhang,Pan Deng
Recent advances in lipid nanoparticle (LNP) delivery systems have enabled the development of mRNA vaccines and oligonucleotide therapeutics. Reliable hepatic in vitro systems are essential for the evaluation of the biodegradation of LNP components. SM-102 is an important ionizable lipid used in Moderna’s LNP-mRNA vaccine. In this study, we compared the metabolism of SM-102 using three in vitro hepatic models, including liver microsomes, 2D hepatocyte cultures and 3D liver spheroids prepared from primary rodent hepatocytes and HepG2 cells. An ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS) method was developed to detect and characterize SM-102 metabolites. A 2,4-dinitrophenylhydrazine (DNPH) derivatization method was developed to further capture and characterize the potential carbonyl products. Following incubation of SM-102 with liver microsomes from human, monkey, dog, rat, and mouse, seven metabolites were identified, with oxidation to carbonyl-containing metabolites representing the predominant pathway. In mouse 2D hepatocytes and 3D liver spheroids, six metabolites were detected, and the major metabolic pathways included N-dealkylation (M6), acetylation (M7), and hydrolysis (M8). In rat 2D hepatocyte cultures, six metabolites were detected, with M6 and M8 as the major metabolites. In contrast, β-oxidation-related metabolites (M10 and M11) were the major metabolites detected in rat 3D hepatocyte spheroids. Comparable metabolic profiles of SM-102 were observed in HepG2 2D cultures and 3D spheroids, with hydrolysis and N-dealkylation as the predominant metabolic pathways. Taken together, this study characterized the metabolic profiles of SM-102 across three in vitro hepatic models, and comparable metabolic profiles were observed between 2D hepatocytes and 3D spheroids prepared from primary mouse hepatocytes and HepG2 cells. These findings provide useful information for selecting appropriate in vitro models to ensure the reliable evaluation of ionizable lipid biodegradation.
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Chao Liu,Yuhao Jiang,Wenliang Xue,Jinyu Liu,Zihao Wang,Jianhong Luo,Xinsong Li
Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential for precise therapeutic outcomes and minimized side effects in various disease models. However, achieving targeted delivery beyond the liver is a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto the head of a cholesterol-like structure and incorporated them as a fifth component into conventional commercial LNPs based on ALC-0315 or SM-102. Selective targeting delivery of mRNA is achieved by adjusting the proportion of the fifth component in the LNP. Specifically, a spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% delivery efficiency, while a lung-targeted 102-Sito-40% formulation achieved up to 78%. Moreover, when this strategy is applied to a self-developed ionizable lipid named U-101 instead of ALC-0315 or SM-102, the targeting delivery efficiencies to the spleen and lungs reach 96 and 71%, respectively. Multiple assessments suggest that inclusion of the fifth component does not compromise LNP stability, as indicated by consistent particle size, polydispersity index (PDI), and encapsulation efficiency. Furthermore, the test results of liver and kidney function and immunogenicity reveal no increase of toxicity in vivo following the introduction of the fifth component. Additional studies on in vitro cytotoxicity, lysosomal escape, and cellular transfection efficiency confirm that the fifth component does not diminish delivery performance. Taken together, the incorporation of ionizable cholesterol analogs leads to targeting of LNP delivery, which features strong organ selectivity, high safety, and suitability for further evaluation.
研究领域:
纳米技术
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药学科学
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分子生物学
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治疗学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Tao Wang,Yang Yan,Tinghao Xu,Xiangyang Li,Cheng Xu,Yushuang Wei,Hong Liu,Kai Yang,Bing Yuan
Polystyrene nanoplastics are ubiquitous environmental pollutants, yet their fundamental physical interactions with cell membranes—and how these interactions alter subsequent cellular uptake mechanisms—remain poorly understood. Here, we interrogate nanoplastic-membrane dynamics using chemically defined model membranes (supported lipid bilayers and giant unilamellar vesicles) and intestinal epithelial cells. We demonstrate that 25 nm polystyrene nanoparticles (PS25) fundamentally perturb lipid bilayers, severely restricting macroscopic membrane fluidity and permanently truncating the mobile lipid fraction (from 96.9% ± 1.7–67.2% ± 1.5%). Correspondingly, PS25 elicits significantly higher cellular internalization, mitochondrial impairment, and cytotoxicity relative to 50 nm particles (PS50). Crucially, we reveal that this massive biophysical membrane remodeling acts as a potent structural trigger for "bystander uptake". Specifically, PS25 facilitates the robust co-internalization of diverse, normally impermeable cargoes (including proteins, peptides, and metal nanoparticles) by 2- to 6-fold across susceptible cell lines. Mechanistic investigations confirm this phenomenon is not driven by chemical carrier-cargo complexation, but by physical membrane deformation that hijacks cholesterol-dependent macropinocytosis and lipid raft-mediated endocytosis. These findings highlight a synergistic mechanism by which nanoplastics can act as physical "entry facilitators", potentiating the intracellular delivery and toxicity of co-existing environmental pollutants, thereby providing essential new insights for comprehensive risk assessment.
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DOI
高影响因子
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