Advanced Healthcare Materials
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2025
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IF 9.6
Weibo Zhang,Chong Chen,Ran Wang,Yixuan Li,Yinhua Zhu,Jiazeng Sun,Yongting Luo,Junjie Luo,Liang Zhao,Yanan Sun,Huiyuan Guo,Hao Zhang,Bing Fang,Yao Hu,Rong Liu,Xiaoyu Wang,Jiayue Guo,Ping Liu,Peng An,Pengjie Wang,Juan Chen,Fazheng Ren
Human serum albumin (HSA) plays an indispensable role as a carrier of endogenous and exogenous substances in vivo. The efficiency of endocytosis determines the transport capacity. However, the potential for enhancing the efficiency of HSA endocytosis remains largely unknown. This research represented a substantial advancement, revealing that Fe 2+ markedly increased HSA endocytosis. Moreover, Fe 2+ facilitated the endocytosis and transport of HSA in vivo. The enhancement in HSA uptake facilitated by Fe 2+ is markedly decreased following iron chelation, indicating a specific interaction between Fe 2 ⁺ and HSA that promoted endocytosis. Moreover, the study elucidated that FcRn and caveolin regulated HSA endocytosis under normal conditions. Yet, in the presence of Fe 2 ⁺, endocytosis shifted toward clathrin- and caveolin-enriched membrane domains, requiring both divalent metal transporter 1 (DMT1) and FcRn for efficient process completion. Thereby a new pathway is discovered for Fe 2+ -dependent HSA endocytosis involving DMT1 and clathrin. This findings highlighted the crucial role of iron in enhancing HSA endocytosis and transport, establishing Fe 2+ as a vital endocytic enhancer that required binding to HSA to substantially improve its uptake. This insight into the mechanism of HSA endocytosis not only expands the understanding of protein transport but also opens new avenues for therapeutic intervention.
研究领域:
生物化学
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细胞生物学
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医学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Zhiyou Wang,Linan Lin,Aidi Huang,Zhiwei Huang,Hanlin Li,Dan Chen,Zepeng Huang,Wen Li,Cai Yuan,Mingdong Huang
Human serum albumin (HSA) is a clinically validated carrier for half-life extension via FcRn recycling, yet conventional N- or C-terminal albumin fusions can compromise fusion-partner activity or increase product heterogeneity. Here we evaluated an internal insertion between HSA residues 363 and 364 using two fusion proteins with distinct sizes and termini geometries: interleukin-2 (IL2, 15.5 kDa) and soluble TNFR2 (sTNFR2, 25 kDa). In HEK293F cells, internal insertion produced predominantly monomeric fusion proteins with reduced fragmentation compared to the N-terminal fusions based on gel filtration and SDS-PAGE profiles. The IL2 internal-insertion fusion (I-IL2) retained activities of binding to CD25-positive cells and stimulating cell proliferation (EC 50 = 9.50 nM). sTNFR2 internal-insertion fusions retained TNFα binding with nanomolar apparent affinities by surface plasmon resonance, while another internal fusion flanked with linkers showing the strongest binding (apparent K D = 9.52 nM) and the highest neutralizing potency in the activity assay (EC 50 = 3.0 nM). For the IL2 fusion, FcRn binding at pH 6.0 was found to be in the micromolar range, with I-IL2 showing stronger apparent binding than N-IL2 under identical assay conditions. Molecular modeling and structural overlays suggested that the inserted domains for all fusions are spatially separated from the FcRn-binding surface of albumin while remaining accessible for receptor binding. Together, these results identify HSA 363–364 as a promising internal insertion site that preserves fusion-partner function.
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Wei Zhang,Wen Guo,Caishun Chen,Meiqi Han,Yuling Mao,Siling Wang
MSN@ME induces immune responses across gastrointestinal, respiratory, and reproductive mucosae. • FcRn mediates intestinal transport of intact OVA/MSN@ME to the lamina propria and lymphatic system. • MSN@ME enhances gut antigen uptake, dendritic cell maturation, and lymphatic targeting. It is imperative to adopt immune strategies that provide effective protection at the mucosal entry points of pathogens. Direct mucosal vaccination can effectively induce local mucosal immune responses and activate systemic mucosal immunity. However, the low uptake of antigens by antigen-presenting cells due to the mucus layer and epithelial barriers limits the effectiveness of vaccines. The neonatal Fc receptor (FcRn), known as a “mucosal gateway,” is thought to enhance drug uptake in intestinal epithelial cells. The study found that milk-derived exosomes (ME) can effectively utilize a “hitchhiking” strategy by encapsulating subunit antigens (such as ovalbumin, OVA) combined with immunostimulatory mesoporous silica nanoparticles (MSN) to create an oral vaccine that efficiently traverses the intestinal epithelial barrier and reaches the mucosal lamina propria. Our findings demonstrate that OVA/MSN@ME effectively maintains the oral stability of antigens and facilitates their translocation to the lamina propria, preliminarily suggesting an FcRn-mediated transport mechanism. This process subsequently triggers robust immune responses within gut-associated lymphoid tissues. These results indicate that the MSN@ME composite system is a promising delivery strategy for targeting mucosal epithelial cells, offering a potent means to enhance mucosal immunity against infectious diseases. Download: Download high-res image (169KB) Download: Download full-size image
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高影响因子
ACS Nano
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2024
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IF 15.8
Jie Wang,Zilong Zhang,Zhuan Zhang,Zhiwen Zou,Yan Zhuo,Chang Liu,Di Nie,Yong Gan,Miaorong Yu
The development of effective oral drug delivery systems for targeted gut-to-liver transport remains a significant challenge due to the multiple biological barriers including the harsh gastrointestinal tract (GIT) environment and the complex protein corona (PC) formation. In this study, we developed ligand-modified nanoparticles (NPs) that enable gut-to-liver drug delivery by crossing the GIT and attenuating PC formation. Specifically, mesoporous silica nanoparticles (MSNs) were functionalized with peptides targeting the neonatal Fc receptor (FcRn), capitalizing on FcRn expression in the small intestine and liver for targeted drug delivery. We showed that MSNs decorated with a small cyclic FcRn binding peptide (MSNs-FcBP) obtained enhanced diffusion in intestinal mucus and superior transportation across the intestine compared to unmodified MSNs and MSNs decorated with a large IgG Fc fragment (MSNs-Fc), which correlated with diminished protein adsorption and weaker interaction with mucin. After entering the blood circulation, reduced serum PC formation by MSNs-FcBP reduces the proteolytic and phagocytic propensity of the reticuloendothelial system, ultimately ameliorating accumulation in hepatocytes. Pharmacokinetic and pharmacodynamic studies in diabetic mice revealed that MSNs-FcBP effectively transported the therapeutic agent exenatide across the intestinal epithelium, leading to a significant hypoglycemic response and improved glucose tolerance. This study underscores the critical role of ligand selection in limiting protein corona formation, thereby significantly enhancing gut-to-liver drug delivery by increasing mucus permeation and minimizing serum–protein interactions. The effective delivery of exenatide in diabetic mice illustrates the potential of this strategy to optimize oral drug bioavailability and therapeutic efficacy.
研究领域:
药学
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纳米技术
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药物递送系统
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生物药剂学
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产品关联
DOI
PubMed
高影响因子
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