消化道结构特征与多肽药物递释系统转运途径研究

Structural Characteristics of the Gastrointestinal Tract and the Transport Pathways of Peptide Drug Delivery Systems

摘要

多肽药物在重大疾病的治疗中展现出巨大潜力，然而其口服递送面临消化道多重生理屏障带来的严峻挑战。为实现多肽药物的口服给药，纳米载体、离子液体、微针、给药装置等口服药物递释系统已受到广泛关注，但目前获批上市的相关产品数量仍较为有限。明晰消化道结构特征和药物递释系统的转运途径将为多肽药物口服制剂的合理化设计提供理论依据。系统梳理了消化道生理结构及其形成的生化屏障与物理屏障，围绕药物递释系统穿透上皮屏障的主要途径，分别阐述跨细胞途径、细胞旁路途径及微皱褶细胞介导的淋巴转运途径的作用机制与调控方法。在此基础上，归纳梳理基于不同转运途径设计的口服多肽递释系统，总结口服给药实现消化道外器官靶向递送的研究发展方向，以期为高效多肽口服递释系统的研发提供理论依据与设计思路。

Abstract

Peptide drugs show great potential in treating critical diseases, yet their oral delivery faces severe challenges due to multiple physiological barriers in the gastrointestinal tract. To achieve the oral administration of peptide drugs, various oral drug delivery systems such as nanocarriers, ionic liquids, microneedles, and delivery devices have attracted extensive attention; however, the number of products currently approved for marketing is still relatively limited. Clarifying the structural characteristics of the gastrointestinal tract and the transport pathways of drug delivery systems can provide a theoretical basis for the rational design of oral peptide drug formulations. This article systematically summarizes the physiological structure of the gastrointestinal tract as well as the biochemical and physical barriers formed thereby. Focusing on the major pathways by which drug delivery systems penetrate the epithelial barrier, it elaborates on the mechanisms and regulatory strategies of transcellular pathway, paracellular pathway and microfold cell-mediated lymphatic transport pathway. On this basis, it sorts out oral peptide delivery systems designed based on different transport pathways, and summarizes the research trends of achieving targeted delivery to extra-intestinal organs via oral administration, aiming to provide theoretical basis and design strategies for developing high-efficiency oral peptide delivery systems.

关键词

多肽药物 / 口服递送 / 消化道结构 / 转运途径 / 纳米载体 / 药物递释系统

Key words

peptide drug / oral delivery / structure of the gastrointestinal tract / transport pathway / nanocarrier / drug delivery system

参考文献

[1] Ensign L M, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers[J].Adv Drug Deliv Rev, 2012, 64(6): 557-570.

[2] Becker H M, Seidler U E. Bicarbonate secretion and acid/base sensing by the intestine[J].Pflügers Arch Eur J Physiol, 2024, 476(4): 593-610.

[3] Collins J T, Nguyen A, Omole A E,et al. Anatomy, Abdomen and Pelvis, Small Intestine [M]. Treasure Island (FL):StatPearls Publishing, 2025.

[4] Brinck J E, Sinha A K, Laursen M F,et al. Intestinal pH: a major driver of human gut microbiota composition and metabolism[J].Nat Rev Gastroenterol Hepatol, 2025, 22(9): 639-656.

[5] Koepsell H. Glucose transporters in the small intestine in health and disease[J].Pflügers Arch Eur J Physiol, 2020, 472(9): 1207-1248.

[6] Wu X, Wu W, Nam J,et al. Intestinal retentive delivery system for improved disease therapy[J].J Control Release, 2025, 384: 113903.

[7] Neupane R, Karthikeyan C, Piedra V,et al. Novel macropinocytosis inducers selectively modulate intracellular delivery of small and macromolecules in cancer cells[J].Int J Biol Macromol, 2025, 322(Pt 3): 146366.

[8] McCoubrey L E, Favaron A, Awad A,et al. Colonic drug delivery: formulating the next generation of colon—targeted therapeutics[J].J Control Release, 2023, 353: 1107-1126.

[9] Vrinda A M, Thangaraju M, Nair S A,et al. Unraveling the role of mucins and gut microbiota in gastrointestinal cancers chemoresistance[J].Biochim Biophys Acta Rev Cancer, 2025, 1880(4): 189385.

[10] Sato H, Yamada K, Miyake M,et al. Recent advancements in the development of nanocarriers for mucosal drug delivery systems to control oral absorption[J].Pharmaceutics, 2023, 15(12): 2708.

[11] Lu Y, Han S, Zhang S,et al. The role of probiotic exopolysaccharides in adhesion to mucin in different gastrointestinal conditions[J].Curr Res Food Sci, 2022, 5: 581-589.

[12] Boegh M, García—Díaz M, Müllertz A,et al. Steric and interactive barrier properties of intestinal mucus elucidated by particle diffusion and peptide permeation[J].Eur J Pharm Biopharm, 2015, 95(Pt A): 136-143.

[13] Dolan B, Ermund A, Martinez—Abad B,et al. Clearance of small intestinal crypts involves goblet cell mucus secretion by intracellular granule rupture and enterocyte ion transport[J].Sci Signal, 2022, 15(752): eabl5848.

[14] Sankova M V, Nikolenko V N, Bolotskaia A A,et al. Paneth cells: recent updates on elucidating therapeutic implications in gastroenterological disease management[J].Curr Med Chem, 2025, 32(42): 9679-9706.

[15] Saint—Denis E, Frintu B, Goldsmith M,et al. Enteroendocrine cell differentiation: implications for human disease[J].Mol Cell Endocrinol, 2025, 607: 112607.

[16] Xiong Z, Zhu X, Geng J,et al. Intestinal Tuft—2 cells exert antimicrobial immunity viasensing bacterial metabolite N—undecanoylglycine[J].Immunity, 2022, 55(4): 686-700.e7.

[17] Schneider C, O’Leary C E, Locksley R M. Regulation of immune responses by tuft cells[J].Nat Rev Immunol, 2019, 19(9): 584-593.

[18] Azkanaz M, Corominas—Murtra B, Ellenbroek S I J,et al. Retrograde movements determine effective stem cell numbers in the intestine[J].Nature, 2022, 607(7919): 548-554.

[19] Brookes S J H, Spencer N J, Costa M,et al. Extrinsic primary afferent signalling in the gut[J].Nat Rev Gastroenterol Hepatol, 2013, 10(5): 286-296.

[20] Sheridan B S, Lefrançois L. Intraepithelial lymphocytes: to serve and protect[J].Curr Gastroenterol Rep, 2010, 12(6): 513-521.

[21] Otani T, Furuse M. Tight junction structure and function revisited[J].Trends Cell Biol, 2020, 30(10): 805-817.

[22] Mayor S, Pagano R E. Pathways of clathrin—independent endocytosis[J].Nat Rev Mol Cell Biol, 2007, 8(8): 603-612.

[23] Xiao W, Jiang W, Chen Z,et al. Advance in peptide—based drug development: delivery platforms, therapeutics and vaccines[J].Signal Transduct Target Ther, 2025, 10(1): 74.

[24] Laurent Q, Martinent R, Lim B,et al. Thiol—mediated uptake[J].JACS Au, 2021, 1(6): 710-728.

[25] Zhuo Y, Luo Z, Zhu Z,et al. Direct cytosolic delivery of siRNA viacell membrane fusion using cholesterol—enriched exosomes[J].Nat Nanotechnol, 2024, 19(12): 1858-1868.

[26] Wang S, Zhang J, Zhou H,et al. The role of protein corona on nanodrugs for organ—targeting and its prospects of application[J].J Control Release, 2023, 360: 15-43.

[27] Yang D, Liu D, Qin M,et al. Intestinal mucin induces more endocytosis but less transcytosis of nanoparticles across enterocytes by triggering nanoclustering and strengthening the retrograde pathway[J].ACS Appl Mater Interfaces, 2018, 10(14): 11443-11456.

[28] Song X, Li R, Deng H,et al. Receptor mediated transcytosis in biological barrier: the influence of receptor character and their ligand density on the transmembrane pathway of active—targeting nanocarriers[J].Biomaterials, 2018, 180: 78-90.

[29] Wu R, Wu Z, Xing L,et al. Mimicking natural cholesterol assimilation to elevate the oral delivery of liraglutide for type II diabetes therapy[J].Asian J Pharm Sci, 2022, 17(5): 653-665.

[30] Zhang R, Deng H, Lin Y,et al. A common strategy to improve transmembrane transport in polarized epithelial cells based on sorting signals: guiding nanocarriers to TGN rather than to the basolateral plasma membrane directly[J].J Control Release, 2021, 339: 430-444.

[31] Tuvia S, Pelled D, Marom K,et al. A novel suspension formulation enhances intestinal absorption of macromolecules viatransient and reversible transport mechanisms[J].Pharm Res, 2014, 31(8): 2010-2021.

[32] Mabbott N A, Donaldson D S, Ohno H,et al. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium[J].Mucosal Immunol, 2013, 6(4): 666-677.

[33] Subramanian D A, Chin A, Shi Y,et al. Identification and validation of cyclic peptides with mucin—selective, location—specific binding in the gastrointestinal tract[J].ACS Nano, 2025, 19(15): 14693-14706.

[34] Ji K, Wei X, Kahkoska A R,et al. An orally administered glucose—responsive polymeric complex for high—efficiency and safe delivery of insulin in mice and pigs[J].Nat Nanotechnol, 2024, 19(12): 1880-1891.

[35] Xiao P, Wang H, Liu H,et al. Milk exosome—liposome hybrid vesicles with self—adapting surface properties overcome the sequential absorption barriers for oral delivery of peptides[J].ACS Nano, 2024, 18(32): 21091-21111.

[36] Zhang Y, Wang Y, Li X,et al. Ligand—modified nanocarriers for oral drug delivery: challenges, rational design, and applications[J].J Control Release, 2022, 352: 813-832.

[37] Xiao X, Zhang L, Ni M,et al. Enhanced oral and pulmonary delivery of biomacromolecules viaamplified transporter targeting[J].J Control Release, 2024, 370: 152-167.

[38] Shan W, Zhu X, Liu M,et al. Overcoming the diffusion barrier of mucus and absorption barrier of epithelium by self—assembled nanoparticles for oral delivery of insulin[J].ACS Nano, 2015, 9(3): 2345-2356.

[39] Buckley S T, Bækdal T A, Vegge A,et al. Transcellular stomach absorption of a derivatized glucagon—like peptide—1 receptor agonist[J].Sci Transl Med, 2018, 10(467): eaar7047.

[40] Bannunah A M, Vllasaliu D, Lord J,et al. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge[J].Mol Pharm, 2014, 11(12): 4363-4373.

[41] Zheng N, Li J, Xu C,et al. Mesoporous silica nanorods for improved oral drug absorption[J].Artif Cells Nanomed Biotechnol, 2018, 46(6): 1132-1140.

[42] Xiao P, Yuan H, Liu H,et al. Modulating the elasticity of milk exosome—based hybrid vesicles to optimize transepithelial transport and enhance oral peptide delivery[J].J Control Release, 2025, 380: 36-51.

[43] Yang D, Feng Y, Yuan Y,et al. Protein coronas derived from mucus act as both spear and shield to regulate transferrin functionalized nanoparticle transcellular transport in enterocytes[J].ACS Nano, 2024, 18(10): 7455-7472.

[44] Xi Z, Ahmad E, Zhang W,et al. Dual—modified nanoparticles overcome sequential absorption barriers for oral insulin delivery[J].J Control Release, 2022, 342: 1-13.

[45] Xing L, Zheng Y, Yu Y,et al. Complying with the physiological functions of Golgi apparatus for secretory exocytosis facilitated oral absorption of protein drugs[J].J Mater Chem B, 2021, 9(6): 1707-1718.

[46] Banerjee A, Ibsen K, Brown T,et al. Ionic liquids for oral insulin delivery[J].Proc Natl Acad Sci U S A, 2018, 115(28): 7296-7301.

[47] Lin P Y, Chen K H, Miao Y B,et al. Phase—changeable nanoemulsions for oral delivery of a therapeutic peptide: toward targeting the pancreas for antidiabetic treatments using lymphatic transport[J].Adv Funct Mater, 2019, 29(13): 1809015.

[48] Han R, He H, Lu Y,et al. Oral targeted drug delivery to post—gastrointestinal sites[J].J Control Release, 2024, 370: 256-276.

[49] Li W, Yang X, Wang M,et al. Development of a cascade—targeting oral vaccine viaglycoprotein 2 on intestinal microfold cells for cancer immunotherapy[J].Nano Lett, 2025, 25(13): 5165-5173.

[50] Zhang Z, Qi J, Lu Y,et al. Peroral targeting of drug micro or nanocarriers to sites beyond the gastrointestinal tract[J].Med Res Rev, 2021, 41(4): 2590-2598.

[51] Kaur R, Shaikh T B, Priya Sripadi H,et al. Nintedanib solid lipid nanoparticles improve oral bioavailability and ameliorate pulmonary fibrosis in vitroand in vivomodels[J].Int J Pharm, 2024, 649: 123644.

[52] Zhang L, Peng H, Feng M,et al. Yeast microcapsule—mediated oral delivery of IL—1β shRNA for post—traumatic osteoarthritis therapy[J].Mol Ther Nucleic Acids, 2021, 23: 336-346.

[53] Zhou X, Zhang X, Han S,et al. Yeast microcapsule—mediated targeted delivery of diverse nanoparticles for imaging and therapy viathe oral route[J].Nano Lett, 2017, 17(2): 1056-1064.

[54] Yang T, Wang A, Nie D,et al. Ligand—switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy[J].Nat Commun, 2022, 13(1): 6649.

[55] Lee J S, Han P, Chaudhury R,et al. Metabolic and immunomodulatory control of type 1 diabetes viaorally delivered bile—acid—polymer nanocarriers of insulin or rapamycin[J].Nat Biomed Eng, 2021, 5(9): 983-997.

[56] Lei T, Yang Z, Jiang C,et al. Mannose—integrated nanoparticle hitchhike glucose transporter 1 recycling to overcome various barriers of oral delivery for Alzheimer, s disease therapy[J].ACS Nano, 2024, 18(4): 3234-3250.

[57] Miao Y B, Chen K H, Chen C T,et al. A noninvasive gut—to—brain oral drug delivery system for treating brain tumors[J].Adv Mater, 2022, 34(21): e2202282.

[58] Wang X, Cui X, Wu J,et al. Peripheral nerves directly mediate the transneuronal translocation of silver nanomaterials from the gut to central nervous system[J].Sci Adv, 2023, 9(27): eadg2252.

[59] Xia D, Wood—Yang A J, Prausnitz M R. Clearing away barriers to oral drug delivery[J].Sci Robot, 2022, 7(70): eade3311.

基金资助

国家自然科学基金资助项目(82473855)

北京市自然科学基金资助项目(Z230017)