{
    "abstract": "Epithelial cell entrance and trans-epithelial transport are two essential processes that directly affect the efficacy of oral delivery of nanocarriers. Herein, a hydroxyethyl starch-based nanocapsule dual decorated with butyrate and octadecylamine (ODA) was first constructed to enhance transporter-mediated endocytosis and trans-epithelial transport, while reducing exenatide (EXT) loss during absorption. The epithelial barrier was then treated with linoleic acid (LA), which functioned as a cell membrane fluidity regulator. This treatment further improved oral delivery efficiency by lowering the energy cost of endocytosis through fluidizing of the cell membrane and increasing monocarboxylate transporter 1 (MCT1) expression on cell surfaces. The findings revealed that LA upregulated MCT1 expression by 3.26-fold, increased the cellular uptake of nanocapsules co-modified with butyrate and ODA by 4.52-fold, decreased ATP consumption for uptake in LA-pretreated Caco-2 cells to only 18.64\u00a0% of that in untreated Caco-2 cells, and increased their transcellular transport by 1.72-fold in a Caco-2/HT29-MTX-E12 co-culture monolayer. Therefore, the oral administration of EXT-loaded Bu-PEG-ODA NCs with LA significantly enhanced the oral bioavailability of EXT (Bu-PEG-ODA NCs group: 10.10\u00a0%, Bu-PEG-ODA NCs\u00a0+\u00a0LA group: 14.84\u00a0%), leading to a significant hypoglycemic effect with a 16.06\u00a0% relative pharmacological availability. This dosing strategy exhibited efficacious blood glucose control and pancreatic function recovery capabilities in the type 2 diabetes rat model. This study presents a unique co-optimization strategy based on two key processes in the oral absorption of nanocarriers, yielding significant advancements in the oral bioavailability of nanomedicines and improving their therapeutic efficacy.",
    "authors": [
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Haoyang",
            "initials": "H",
            "lastname": "Yuan"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Peifu",
            "initials": "P",
            "lastname": "Xiao"
        },
        {
            "affiliation": "Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Fan",
            "initials": "F",
            "lastname": "Wang"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Chen",
            "initials": "C",
            "lastname": "Guo"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Shu",
            "initials": "S",
            "lastname": "Pan"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Mai",
            "initials": "M",
            "lastname": "Jiang"
        },
        {
            "affiliation": "Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Shicheng",
            "initials": "S",
            "lastname": "Hou"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Yunong",
            "initials": "Y",
            "lastname": "Sun"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Yibo",
            "initials": "Y",
            "lastname": "Wang"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Yu",
            "initials": "Y",
            "lastname": "Zhang"
        },
        {
            "affiliation": "School of Functional Food and Wine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Tian",
            "initials": "T",
            "lastname": "Yin"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.",
            "firstname": "Haibing",
            "initials": "H",
            "lastname": "He"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China. Electronic address: jxgou_syphu@163.com.",
            "firstname": "Jingxin",
            "initials": "J",
            "lastname": "Gou"
        },
        {
            "affiliation": "Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China. Electronic address: tanglab@126.com.",
            "firstname": "Xing",
            "initials": "X",
            "lastname": "Tang"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2025 Elsevier B.V. All rights reserved.",
    "doi": "10.1016/j.jconrel.2025.113744",
    "journal": "Journal of controlled release : official journal of the Controlled Release Society",
    "keywords": [
        "Cell membrane fluidity",
        "Cellular uptake",
        "Nanocapsules",
        "Oral bioavailability",
        "Type 2 diabetes"
    ],
    "methods": null,
    "publication_date": "2025-04-18",
    "pubmed_id": "40246242",
    "results": null,
    "title": "Linoleic acid co-administration promotes oral delivery of exenatide-loaded butyrate-decorated nanocapsules.",
    "xml": "<Element 'PubmedArticle' at 0x788504866610>"
}