药学学报

Adhesion strategy	Drug/nano-formulation	Material	Advantage	Ref.
Electrostatic incorporation	Vinorelbine; liposomes	Chitosan	Improved bioavailability by 2.1-fold compared to the vinorelbine solution	[42]
	Insulin; nanoparticles	Chitosan; PLGA	Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration	[43]
	Gefitinib; nanoparticles	CMC; F68; PLGA	Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group	[44]
Bonding force adhesion	Calcitonin; nanoparticles	PAA	Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin	[45]
	Acetaminophen; nanoparticles	Chitosan; PLGA	Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight	[46]
	Sitagliptin; nanoparticles	HPMC; PLGA	Prolonged adhesion duration and enhanced mucoadhesion	[47]
Thiolation strategy	-; nanoparticles	PAA; cysteine	Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group	[48]
	-; nanoparticles	Chitosan; TBA	Significantly enhanced mucoadhesive property of PIBCA-NPs	[49]

Adhesion strategy

Drug/nano-formulation

Material

Advantage

Ref.

Electrostatic incorporation

Vinorelbine; liposomes

Chitosan

Improved bioavailability by 2.1-fold compared to the vinorelbine solution

[42]

Insulin; nanoparticles

Chitosan; PLGA

Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration

[43]

Gefitinib; nanoparticles

CMC; F68; PLGA

Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group

[44]

Bonding force adhesion

Calcitonin; nanoparticles

PAA

Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin

[45]

Acetaminophen; nanoparticles

Chitosan; PLGA

Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight

[46]

Sitagliptin; nanoparticles

HPMC; PLGA

Prolonged adhesion duration and enhanced mucoadhesion

[47]

Thiolation strategy

-; nanoparticles

PAA; cysteine

Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group

[48]

-; nanoparticles

Chitosan; TBA

Significantly enhanced mucoadhesive property of PIBCA-NPs

[49]

Adhesion strategy	Drug/nano-formulation	Material	Advantage	Ref.
Electrostatic incorporation	Vinorelbine; liposomes	Chitosan	Improved bioavailability by 2.1-fold compared to the vinorelbine solution	[42]
	Insulin; nanoparticles	Chitosan; PLGA	Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration	[43]
	Gefitinib; nanoparticles	CMC; F68; PLGA	Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group	[44]
Bonding force adhesion	Calcitonin; nanoparticles	PAA	Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin	[45]
	Acetaminophen; nanoparticles	Chitosan; PLGA	Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight	[46]
	Sitagliptin; nanoparticles	HPMC; PLGA	Prolonged adhesion duration and enhanced mucoadhesion	[47]
Thiolation strategy	-; nanoparticles	PAA; cysteine	Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group	[48]
	-; nanoparticles	Chitosan; TBA	Significantly enhanced mucoadhesive property of PIBCA-NPs	[49]

Adhesion strategy

Drug/nano-formulation

Material

Advantage

Ref.

Electrostatic incorporation

Vinorelbine; liposomes

Chitosan

Improved bioavailability by 2.1-fold compared to the vinorelbine solution

[42]

Insulin; nanoparticles

Chitosan; PLGA

Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration

[43]

Gefitinib; nanoparticles

CMC; F68; PLGA

Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group

[44]

Bonding force adhesion

Calcitonin; nanoparticles

PAA

Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin

[45]

Acetaminophen; nanoparticles

Chitosan; PLGA

Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight

[46]

Sitagliptin; nanoparticles

HPMC; PLGA

Prolonged adhesion duration and enhanced mucoadhesion

[47]

Thiolation strategy

-; nanoparticles

PAA; cysteine

Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group

[48]

-; nanoparticles

Chitosan; TBA

Significantly enhanced mucoadhesive property of PIBCA-NPs

[49]

Penetration strategy	Drug/nano-formulation	Material	Advantage	Ref.
Hydrophilic penetration	DOX; SLNs	PEG	Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group	[60]
	-; silica nanoparticles	PMOZ	Significantly enhanced mucus-penetrating capability of silica nanoparticles	[61]
	Insulin; nanoparticles	pHPMA; TMC	Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles	[62]
Inert penetration	RGH; mesoporous silica nanoparticles	PEG; CPPs	Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies	[63]
	CyA; liposomes	F127	Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes	[64]
	-; nanoparticles	PDA; PLGA	Faster mucus penetration ability compared with unmodified PLGA nanoparticles	[65]
	-; nanoemulsions	Soy lecithin	Comparable mucus permeability to the PEG-modified group, and higher cell uptake	[66]
Mucolytic penetration	-; SEDDS	Trypsin	Increased mucus permeability by 2.6-fold compared with unmodified SEDDS	[67]
	-; SEDDS	PAP	Significantly superior mucus-penetrating capability compared to the enzyme-unmodified SEDDS	[68]

Penetration strategy

Drug/nano-formulation

Material

Advantage

Ref.

Hydrophilic penetration

DOX; SLNs

PEG

Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group

[60]

-; silica nanoparticles

PMOZ

Significantly enhanced mucus-penetrating capability of silica nanoparticles

[61]

Insulin; nanoparticles

pHPMA; TMC

Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles

[62]

Inert penetration

RGH; mesoporous silica nanoparticles

PEG; CPPs

Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies

[63]

CyA; liposomes

F127

Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes

[64]

-; nanoparticles

PDA; PLGA

Faster mucus penetration ability compared with unmodified PLGA nanoparticles

[65]

-; nanoemulsions

Soy lecithin

Comparable mucus permeability to the PEG-modified group, and higher cell uptake

[66]

Mucolytic penetration

-; SEDDS

Trypsin

Increased mucus permeability by 2.6-fold compared with unmodified SEDDS

[67]

-; SEDDS

PAP

Significantly superior mucus-penetrating capability compared to the enzyme-unmodified SEDDS

[68]

Penetration strategy	Drug/nano-formulation	Material	Advantage	Ref.
Hydrophilic penetration	DOX; SLNs	PEG	Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group	[60]
	-; silica nanoparticles	PMOZ	Significantly enhanced mucus-penetrating capability of silica nanoparticles	[61]
	Insulin; nanoparticles	pHPMA; TMC	Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles	[62]
Inert penetration	RGH; mesoporous silica nanoparticles	PEG; CPPs	Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies	[63]
	CyA; liposomes	F127	Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes	[64]
	-; nanoparticles	PDA; PLGA	Faster mucus penetration ability compared with unmodified PLGA nanoparticles	[65]
	-; nanoemulsions	Soy lecithin	Comparable mucus permeability to the PEG-modified group, and higher cell uptake	[66]
Mucolytic penetration	-; SEDDS	Trypsin	Increased mucus permeability by 2.6-fold compared with unmodified SEDDS	[67]
	-; SEDDS	PAP	Significantly superior mucus-penetrating capability compared to the enzyme-unmodified SEDDS	[68]

Penetration strategy

Drug/nano-formulation

Material

Advantage

Ref.

Hydrophilic penetration

DOX; SLNs

PEG

Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group

[60]

-; silica nanoparticles

PMOZ

Significantly enhanced mucus-penetrating capability of silica nanoparticles

[61]

Insulin; nanoparticles

pHPMA; TMC

Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles

[62]

Inert penetration

RGH; mesoporous silica nanoparticles

PEG; CPPs

Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies

[63]

CyA; liposomes

F127

Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes

[64]

-; nanoparticles

PDA; PLGA

Faster mucus penetration ability compared with unmodified PLGA nanoparticles

[65]

-; nanoemulsions

Soy lecithin

Comparable mucus permeability to the PEG-modified group, and higher cell uptake

[66]

Mucolytic penetration

-; SEDDS

Trypsin

Increased mucus permeability by 2.6-fold compared with unmodified SEDDS

[67]

-; SEDDS

PAP

Significantly superior mucus-penetrating capability compared to the enzyme-unmodified SEDDS

[68]

纳米制剂克服胃肠道黏液屏障的作用机制及递送策略研究进展

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胡文慧 , 李芳 , 邹海滨 , 岳鹏飞 , 陈颖翀 ^*

药学学报 | 综述 2026,61(4): 1166-1179

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药学学报 |综述 2026 , 61 (4) : 1166 -1179

纳米制剂克服胃肠道黏液屏障的作用机制及递送策略研究进展

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胡文慧, 李芳, 邹海滨, 岳鹏飞, 陈颖翀^*

作者信息

江西中医药大学, 现代中药制剂教育部重点实验室, 江西南昌 330004

通讯作者:

陈颖翀, E-mail: yc_chen1020@163.com

作者简介:

作者贡献:

胡文慧负责文献调研与文章撰写; 李芳、邹海滨负责文章排版与文献整理; 岳鹏飞负责对文章进行指导完善; 陈颖翀负责文章选题建议、思路设计与文章修改。

Advances in mechanisms and delivery strategies of nano-formulations for overcoming the gastrointestinal mucus barrier

Wen-hui HU, Fang LI, Hai-bin ZOU, Peng-fei YUE, Ying-chong CHEN^*

Affiliations

Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China

出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-1034

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摘要

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胃肠道黏液作为胃肠道的关键生理屏障, 其高度糖基化的黏蛋白网状结构阻碍了颗粒及药物分子向肠上皮细胞的转运。在口服递药系统中, 有效克服胃肠道黏液屏障是实现药物高效吸收的首要环节。一方面, 持续分泌的黏液层凭借其剪切稀化流变特性, 能够快速清除未能有效穿透的颗粒; 另一方面, 大分子药物由于其分子尺寸超过黏液孔隙尺寸, 难以实现跨黏液层扩散。此外, 部分小分子药物也可能因与黏液层成分发生相互作用而滞留于黏液层中, 或因黏液层持续分泌的动态更新系统而被清除, 从而导致药物递送效率降低。因此, 提升药物的黏液穿透能力成为提高其口服生物利用度的关键策略。本文系统综述了胃肠道黏液的组成与结构、理化性质、屏障特性及其影响药物口服吸收的作用和机制, 并探讨了基于纳米技术的药物递送策略以克服黏液屏障。旨在为增强药物黏液渗透性、提高口服生物利用度, 以及设计高效穿透黏液屏障的纳米制剂提供理论依据与设计指导。

关键词

口服给药 / 黏液屏障 / 黏液黏附 / 黏液穿透 / 纳米制剂

Abstract

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Gastrointestinal mucus constitutes a critical physiological barrier in the gastrointestinal tract. Its highly glycosylated mucin network effectively hinders the transport of particles and drug molecules toward the intestinal epithelium. In oral drug delivery, effectively overcoming this gastrointestinal mucus barrier is essential for achieving efficient drug absorption. On one hand, the continuously secreted mucus layer rapidly clears ineffectively penetrating particles due to its shear-thinning rheological property. On the other hand, macromolecular drugs face significant challenges in cross-mucus diffusion when their molecular size exceeds the mucus mesh pore size. Furthermore, certain small-molecule drugs can also be retained within the mucus layer through physicochemical interactions with its components, or rapidly eliminated by the dynamic turnover of the continuously secreted mucus, consequently leading to reduced drug delivery efficiency. Therefore, enhancing the mucus-penetrating capability of drug molecules is crucial for improving their oral bioavailability. This article systematically reviews the composition, structure, physicochemical properties, and barrier characteristics of gastrointestinal mucus, along with its barrier mechanisms affecting oral drug absorption. Additionally, it discusses nanotechnology-based drug delivery strategies designed to overcome the mucus barrier. The review aims to provide a theoretical basis and design principles for enhancing mucus permeability, improving oral bioavailability, and developing highly efficient mucus-penetrating nano-formulations.

Key words

oral delivery / mucus barrier / mucus adhesion / mucus penetration / nano-formulation

引用本文

胡文慧, 李芳, 邹海滨, 岳鹏飞, 陈颖翀. 纳米制剂克服胃肠道黏液屏障的作用机制及递送策略研究进展. 药学学报, 2026 , 61 (4) : 1166 -1179 . DOI: 10.16438/j.0513-4870.2025-1034

Wen-hui HU, Fang LI, Hai-bin ZOU, Peng-fei YUE, Ying-chong CHEN. Advances in mechanisms and delivery strategies of nano-formulations for overcoming the gastrointestinal mucus barrier[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1166 -1179 . DOI: 10.16438/j.0513-4870.2025-1034

正文

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口服给药作为临床中最常用的给药途径, 相较于其他给药方式具有安全性高、使用便利、患者依从性高与成本低等显著优势。药物发挥药效需经胃肠道吸收进入血液循环, 然而这一过程面临多重生理屏障的严峻挑战。对于水溶性大分子药物(如蛋白质、多肽类药物) 而言, 其分子尺寸超过黏液孔隙尺寸, 且缺乏特异性转运蛋白介导跨膜渗透, 导致跨黏液层扩散率不足; 疏水性小分子药物(如小分子抗癌药物、抗感染药物) 虽可通过被动扩散穿透细胞膜, 但其水溶性极低, 在胃肠道环境中难以有效溶解, 进而导致生物利用度普遍较低^[1]。

此外, 口服药物进入胃肠道后, 在吸收及起效过程中, 除受肝脏首过效应影响外, 还受到多种胃肠道生理屏障的限制^[2]。其中黏液屏障主要由高度糖基化的黏蛋白构成, 是隔离外来物质与肠上皮的第一道防线。此黏液屏障在保护肠上皮免受酸、酶破坏及病原体的入侵的同时^[3], 还具有润滑胃肠道的作用, 可避免肠上皮细胞在消化过程中受到机械性剪切损伤^[4]。作为覆盖于肠上皮表面的凝胶型网状结构, 肠黏液屏障通过持续分泌与脱落实现自我更新, 约4~6 h^[5]内即可完成一次更新。这种动态更新机制能有效清除截留于其中的外来物质和病原体, 但同时也会将药物颗粒识别为异物并加以清除, 阻碍药物向肠上皮细胞的扩散与吸收过程^[6]。因此, 胃肠道黏液屏障的存在显著影响药物的体内过程和疗效发挥, 在口服药物制剂设计中, 如何克服或规避黏液屏障的限制已成为关键考量因素。

纳米制剂作为新一代药物递送系统, 能够从多维度突破口服给药的关键瓶颈, 其核心优势主要包括: ①显著提高包载药物的溶解度^{[7, 8]}, 并有效防止药物在胃肠道中被酶降解; ②具备良好的黏液穿透能力, 可延长药物在胃肠道中的滞留时间^[9]; ③实现药物的缓慢与持续释放, 并促进药物跨膜转运^[10]。这些特性使得纳米制剂在提升多种药物口服生物利用度方面展现出广阔的应用前景。

目前常见的纳米制剂包括纳米粒、聚合物胶束、脂质体、固体脂质纳米粒、无机纳米粒和自乳化给药系统等。在影响药物口服生物利用度的诸多因素中, 能否高效跨越胃肠道黏液屏障是关键决定因素之一。本文系统综述胃肠道黏液的组成与结构、理化性质、屏障特性及其影响药物口服吸收的作用和机制, 并探讨基于纳米技术的递送策略, 以克服该屏障, 为增强药物黏液渗透性、提高口服生物利用度及设计高效黏液穿透型纳米制剂提供理论参考与设计思路。

1　胃肠道黏液的组成与结构

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1.1　黏液的组成

胃肠道黏液是覆盖于胃肠道黏膜上皮细胞表面的复杂水凝胶体系, 主要由水、黏蛋白、碳水化合物、脂质、电解质、DNA、细菌和脱落的细胞碎片等成分组成。其中水分占比最高, 达90%~95%; 黏蛋白和脂类占0.5%~5%, 无机盐占0.5%~1%^[11]。作为一种动态更新的生物屏障, 胃肠道黏液具有独特的黏弹性和黏附性, 并呈现典型的选择性屏障特征。这种特性使其能够有效阻挡大部分细菌、病毒等病原体和有害物质的入侵, 同时允许小分子物质(如水、离子、营养物质) 及药物小分子通过自由扩散作用实现跨黏液转运^{[12, 13]}。

1.2　黏液的结构

黏蛋白是黏液中最主要的有机成分, 为高度糖基化的大分子糖蛋白, 主要包括分泌型黏蛋白和跨膜型黏蛋白^[14]。①分泌型黏蛋白(如小肠MUC2、胃MUC5AC) 由杯状细胞分泌至肠腔后, 经水合解聚形成凝胶网状结构, 构成黏液屏障的主要“支架”^[15]; ②跨膜型黏蛋白(MUC1、MUC3、MUC4等) 位于上皮细胞顶端, 其跨膜结构域通过疏水相互作用锚定于细胞膜, 为胃肠道上皮细胞表层构建稳定的微环境^[16]。

黏蛋白单体通过共价与非共价作用交联形成三维网络结构, 其亲水糖链通过水合作用使网络高度膨胀, 促进黏液层形成水凝胶状。结构上, 靠近上皮细胞的黏液由黏蛋白和多糖构成紧密黏附层, 其上方则为疏松黏附层^[17]。黏蛋白中糖基化基团的负电性、非糖基化蛋白链的疏水区, 以及黏蛋白纤维交织形成的物理网络, 共同构成了黏液渗透屏障的结构基础^[11]。

2　黏液的理化性质影响药物口服吸收的作用及机制

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胃肠道黏液作为动态生物屏障, 其核心理化性质(如孔径结构、pH值、离子强度及黏弹性) 通过多重机制协同调控药物递送系统的跨屏障的转运效率。黏液可通过静电相互作用、范德华力、疏水作用、氢键及链缠结等多种物理化学作用捕获药物分子或颗粒, 使其滞留于黏蛋白构成的致密网络中, 显著降低其扩散速率^[18]。值得注意的是, 药物跨屏障扩散效率不仅取决于黏液本身的性质, 还受颗粒尺寸、表面性质等因素的影响^[19]。

2.1　孔径与尺寸筛分效应

黏液对药物的物理阻隔主要源于黏蛋白纤维网络及其孔隙的筛分效应。该网络孔径在胃肠道内动态变化, 通常介于100~500 nm, 并受黏液层厚度、水合状态及生理环境影响^[20]。这种结构决定了药物的尺寸依赖性扩散: 小分子物质可相对自由地穿透黏液, 而较大的分子(如球状蛋白) 则扩散受阻。具体而言, 颗粒在黏液中的迁移率随尺寸增大而显著降低^[21]。研究发现, 粒径小于200 nm的纳米颗粒更容易通过黏液孔隙但即使是粒径达到或超过100 nm的颗粒, 其扩散速率也可被黏液降低数千倍^[22]。该尺寸效应的关键在于, 黏液纤维网络对小尺寸颗粒的物理筛分作用较弱, 使其不易被截留。

2.2　多价结合效应

除物理筛分外, 黏蛋白链上的高密度疏水区域及纤维柔韧性, 使其能与不同电荷或疏水性表面的颗粒发生多重、低亲和力的相互作用^[12]。尽管单个作用力较弱, 但大量作用位点产生的累积效应仍能协同阻滞颗粒移动, 此机制被称为多价结合效应。该效应显著增强黏液对颗粒的固定与捕获能力, 是阻碍药物递送系统扩散的另一关键机制。

2.3　pH值

胃肠道各区段的黏液pH环境存在显著差异。口服药物首先面临胃部的强酸性环境(pH约1~2)。值得注意的是, 胃腔至黏膜上皮表面存在显著的pH梯度: 管腔侧极低, 而上皮表面的黏液层因碳酸氢盐(HCO₃^-) 分泌而形成相对中性的微环境(pH约6)。药物进入小肠后, pH在十二指肠区域被局部中和(约6.1), 并沿远端逐渐升高, 结肠和直肠pH可达7~8^[13]。pH的变化是影响药物扩散行为的关键因素。其通过改变黏蛋白糖基化区域的静电荷、促进疏水结构域暴露及影响非共价相互作用等方式, 调控黏液的构象、黏弹性和通透性^{[13, 23]}。

2.4　离子强度

黏液中的离子强度受上皮离子通道机制的调控^[13], 包括囊性纤维化跨膜传导调节因子(cystic fibrosis transmembrane conductance regulator, CFTR)、上皮细胞钠离子通道(epithelial sodium channel, ENaC) 等, 对黏液的流变学性质和药物扩散至关重要。正常生理状态下, 黏液的形成依赖于Ca²⁺介导的cAMP依赖性HCO₃^-分泌与胞吐作用^[24]。其中, HCO₃^-在黏蛋白的水合过程中起关键作用: 通过减少黏蛋白中Ca²⁺的交联作用来降低黏液黏度。而CFTR通道不仅直接介导Cl^-和HCO₃^-跨上皮细胞的顶膜转运, 还可间接下调ENaC的活性, 二者协同维持黏液的离子环境与水合状态^{[24, 25]}。

2.5　黏弹性

黏弹性是胃肠道黏液最核心的理化特性。黏液作为典型的非牛顿流体, 表现出剪切稀化特性(表观黏度随剪切速率增大而降低)^[26], 使其在润滑肠道的同时构成有效物理屏障^[26]。黏液的黏弹性源于黏蛋白通过共价与非共价作用构建的致密三维网络, 其机械强度取决于糖苷侧链间的交联缠绕程度^[27]。水分、无机盐含量、pH值和离子强度等环境因素也对黏弹性具有重要调控作用^[28], 尤以pH值和离子强度的影响最为显著。

2.5.1　pH值的调控作用

pH值是黏液构象和黏弹性的关键调控因子。在胃黏液的酸性环境(低pH) 下, 黏蛋白糖基化区域负电荷减少, 这可能暴露更多疏水结构域并促进氢键形成。这些变化协同增强了黏蛋白网络交联密度, 显著提高黏弹性^[13]。例如, 有研究表明, 在pH为3的酸性环境中, 带电粒子的扩散率均显著低于中性聚乙二醇化粒子, 而在pH为7的中性环境下, 各类粒子则近乎自由扩散^[23]。

2.5.2　离子强度的调控作用

离子强度对黏液黏弹性具有显著调节作用。宏观上表现为离子浓度升高通常导致黏度降低^[26], 其核心机制在于: 高离子强度可减弱黏蛋白分子间及黏蛋白与带电药物载体之间的静电相互作用, 从而削弱黏蛋白网络的内聚力, 降低其物理阻力。这种影响对于带电药物粒子的扩散尤为显著。高浓度盐能通过电荷屏蔽效应削弱带电粒子与黏蛋白间的静电吸引, 显著提高其扩散率, 而对中性粒子的影响则很小^[23]。

3　黏液的屏障特性影响纳米制剂跨黏液屏障的作用机制

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胃肠道黏液层是覆盖于上皮组织表面的致密凝胶层, 构成了一道关键性的选择性屏障。它在允许气体、水分和营养物质交换的同时, 能有效阻挡大部分细菌和病原体的入侵^[29]。然而, 这种保护功能也成为口服药物吸收的主要物理化学屏障。其阻碍作用主要体现在两方面: ①通过持续的分泌、脱落与更新机制迅速清除截留的外来物质(包括药物); ②其固有的亲水性、高黏滞性及复杂的理化性质显著阻碍药物分子从肠腔向吸收上皮细胞的扩散转运, 对于疏水性药物分子和颗粒型递送系统的限制尤为突出^[30]。当药物粒子与黏液层发生相互作用并试图穿透该屏障时, 其扩散过程将面临以下3类典型障碍(图1)。

3.1　动态屏障

黏液层的动态更新特性是其构成药物递送屏障的首要因素。在生理状态下, 杯状细胞每天分泌近10 L黏液, 其中约9.8 L被消化系统重吸收循环利用, 剩余部分则随粪便、呼吸道分泌物(如痰液、唾液、鼻腔分泌物)、生殖道分泌物、泪液等途径排出体外^[31]。黏液通过“分泌—重吸收—排泄”的动态平衡实现持续更新, 迅速清除截留的外来物质。杯状细胞在肠道中的分布并不均匀, 进一步导致黏液分泌速率的区域异质性: 由于杯状细胞密度沿肠道下行逐渐升高(如十二指肠约4%至远端结肠约16%), 黏液分泌速率也相应增加^[32]。

黏液层可分为疏松黏附层(外层) 与紧密黏附层(内层), 两者更新特性的差异构成了药物渗透的“双重动态阻碍”。疏松黏附层由于持续受胃肠道机械蠕动和酶解作用的影响, 更新周期极短(1~5 h)。药物在此层虽可短暂滞留, 但绝大多数因快速脱落更新而被清除, 难以实现持续递送或有效深层渗透。与之相反, 紧密黏附层因与上皮细胞紧密黏附, 更新周期显著延长(数小时至数天)^[5]。尽管更新缓慢延长了药物接触时间, 但其高黏滞性却显著限制了药物分子向上皮细胞的扩散速率。此外, 肠道蠕动进一步加速黏液层流动更新, 缩短了药物在作用部位的滞留时间。

3.2　空间屏障

黏液的空间屏障功能核心源于黏蛋白网络的尺寸排阻效应。这种高度水合的三维网状结构可视为一个“分子筛”, 其网孔大小不均一, 例如胃黏液平均孔径约500 nm, 而结肠黏液平均孔径约200 nm^{[3, 33]}。尺寸依赖性决定了物质的扩散行为: 小分子物质可通过网络间隙的低黏度孔道自由扩散, 而尺寸大于网格孔径的化合物则被物理截留, 难以有效穿透。

已有研究证实, 颗粒在黏液中的扩散能力随其粒径增大而显著降低^[21]。通常, 粒径 > 500 nm的颗粒易被截留; 而粒径在100~200 nm内的小颗粒具有较高的扩散系数和穿透能力, 其流动性主要取决于其表面性质^{[34, 35]}。此外, 黏液的高黏滞性和上皮表面紧密黏附层的协同作用, 进一步增强了空间屏障对粒子转运的阻滞效应^[12]。

3.3　物理化学相互作用屏障

黏液的复杂化学组成是其物理化学屏障功能的物质基础。它通过静电相互作用、范德华力、疏水作用、氢键及黏蛋白链缠结等多种机制与外来颗粒发生相互作用。一方面, 黏蛋白寡糖链富含的羟基、羧基及硫酸基等基团, 提供了氢键和离子相互作用的结合位点^[12]。由于黏液整体带负电, 带正电荷颗粒易被吸附和滞留; 另一方面, 黏蛋白链上分布的高密度疏水区域可与疏水性微粒之间产生显著疏水相互作用, 这也是黏液捕获病原体的重要途径^[36]。这些多重的化学相互作用与黏蛋白长链缠绕和交联形成的致密三维网状结构, 共同赋予黏液强大的“捕获”能力, 被捕获的微粒最终将随黏液层的持续更新与脱落而被清除^{[18, 37]}。

该网状“过滤器”显著降低了颗粒的扩散速率与渗透效率。其中, 颗粒表面性质, 尤其是电荷分布, 是影响其渗透行为的关键因素: 由于黏液整体带负电, 带正电荷的颗粒易被吸附并滞留于黏液层中, 带负电荷则易被排斥, 而电中性颗粒既不易被吸附也不被排斥, 因此穿透黏液屏障的阻力最小^[19]。研究证实, 表面中性的共聚物和两性离子功能化纳米粒(具中性、亲水性表面) 均表现出高黏液渗透性, 有效增强了药物摄取和吸收^{[38, 39]}。

4　纳米制剂跨黏液屏障的机制与策略

收起

药物载体克服黏液屏障的核心挑战在于平衡其黏附性与穿透性。纳米载体通常难以抵御强烈的胃肠道排空和黏液清除机制, 导致药物在被吸收前即被快速清除^[40]。因此, 适当增强载体的黏附性有利于延长其滞留时间, 从而提高药物吸收。然而, 黏附型载体受限于黏液快速更新与清除的特性; 过强的黏附性还会削弱穿透能力, 反而可能限制药物生物利用度的提升。因此, 理想的口服纳米递药系统需兼具良好的黏液穿透能力, 能够快速穿越黏液屏障, 抵达紧密黏附层或上皮细胞表面, 以实现高效药物递送。

目前, 纳米递药系统跨黏液屏障转运的策略主要分为以下两类(图2): ①黏液黏附型策略: 如通过静电吸附、非特异性结合力修饰及巯基化等方法增强黏附; ②黏液穿透型策略: 涵盖表面亲水化修饰、惰性涂层技术及黏液溶解等方法。此外, 近年来研究者还开发了若干新型递送策略, 以协同克服多重生理屏障。本节系统总结了国内外相关研究进展, 旨在为高效口服纳米递药系统的设计提供理论参考与实践指导。

4.1　黏液黏附型策略

黏液黏附型策略旨在通过增强纳米制剂与黏液层之间的相互作用(如静电吸附、氢键、疏水作用、范德华力、共价键结合), 提高其黏附能力^[41]。该策略的核心目标在于延长纳米制剂在黏液中的滞留时间, 避免被胃肠道排空或黏液更新机制快速清除, 从而提高药物吸收。实现路径主要包括: 选用生物黏附材料(如纤维素衍生物、合成或天然高分子等) 或对纳米载体表面进行特定化学修饰等实现牢固黏附。表1^[42-49]总结了目前常见的各类黏液黏附型纳米递药系统及其优点。

4.1.1　静电吸附策略

静电吸附是黏液黏附型策略中的经典机制, 其核心在于利用带正电的纳米载体与黏液层中富含负电基团的黏蛋白之间的强静电相互作用, 实现载体在黏液中的有效滞留。

壳聚糖及其衍生物是最广泛应用的阳离子型黏附材料^[50]。壳聚糖在酸性环境(pH < 6) 中氨基发生质子化而带正电, 能通过静电作用牢固结合黏液组分, 从而显著增强黏附^[51]。Guo等^[42]制备了壳聚糖修饰的载长春瑞滨的脂质体。体外黏附实验证实, 壳聚糖修饰后的脂质体黏附性能显著提升, 且其口服生物利用度相较于长春瑞滨溶液提高了2.1倍。Zhang等^[43]制备了壳聚糖修饰的载胰岛素的聚乳酸-羟基乙酸共聚物[poly (lactic-co-glycolic acid), PLGA] 纳米粒(nanoparticles, NPs), 该制剂表现出良好的生物黏附性: 给药8 h后仍可在大鼠肠道中检测到明显荧光信号, 而未修饰的PLGA纳米粒组在7 h后信号已基本消失。

然而, 壳聚糖的黏附能力高度依赖环境pH, 这限制了其在胃肠道全域的有效应用。为克服这一局限, 研究人员开发了N-三甲基壳聚糖(N, N, N-trimethyl chitosan, TMC)、羧甲基壳聚糖(carboxymethyl chitosan, CMC) 等化学改性衍生物, 以期在更宽的pH范围内维持良好的黏附性能^[41]。Wang等^[44]制备了CMC修饰的载吉非替尼的F68/PLGA-NPs, 该制剂在小肠中显示出高黏附性, 其生物利用度较未修饰组提高了约1.6倍。

静电吸附策略通过阳离子型黏附材料与黏蛋白之间的强静电作用, 能够有效延长纳米载体在黏液中的滞留时间, 提升药物的口服生物利用度。然而, 其有效性高度依赖于载体表面的正电荷密度。高正电荷密度在增强黏附性的同时, 也伴随着潜在的细胞毒性风险, 这在很大程度上限制了其临床转化潜力。

4.1.2　结合力黏附策略

纳米载体可通过非共价结合力(如缠结作用、氢键、疏水相互作用) 与黏液形成牢固的物理黏附, 从而增强在黏液层的滞留, 这是静电相互作用之外的另一种重要黏附策略^[34]。常见的结合力黏附材料包括纤维素衍生物[如羟丙甲纤维素(hydroxypropyl methylcellulose, HPMC)] 和合成聚合物[如聚乳酸、聚癸二酸、PLGA、聚乙烯醇(polyvinyl alcohol, PVA)、聚丙烯酸酯[poly (acrylic acid), PAA] 等], 它们在口服纳米递药系统中已展现出良好的应用潜力^{[34, 52]}。

这类聚合物的黏附机制往往是多种分子间作用力的综合体现。以PAA为例, 其黏附主要来源于长聚合物链和黏蛋白纤维之间的物理缠结和氢键作用^{[52, 53]}。聚合物链缠结能力与分子质量密切相关, 研究表明有效黏附的分子质量阈值为100 000^[54]。在各类PAA中, 卡波姆980因其具有较高的分子质量, 能与黏蛋白形成更强的缠结和交联, 因此表现出最优的黏附性能^[55]。Makhlof等^[45]利用PAA修饰的载降钙素的纳米粒, 其黏附性显著优于降钙素溶液, 有效提高了药物的口服吸收。

复合型黏附聚合物修饰能够进一步提升纳米载体的黏附性与稳定性。Al-Nemrawi等^[46]研究发现, 采用壳聚糖修饰载对乙酰氨基酚的PLGA-NPs显著增强了其生物黏附性, 且该增强效应随壳聚糖浓度和分子质量的增加而增强。Nair等^[47]制备了载西他列汀的HPMC和PLGA复合型黏附纳米粒。体外黏膜黏附实验结果显示, 对照组的药物在5 h后已无法从内层黏膜表面检出, 而复合纳米粒组在10 h后仍有21.98%的药物滞留, 表明其黏附时间显著延长、黏附性能优异。

结合力黏附策略通过聚合物材料的多种非共价相互作用, 为延长纳米载体在黏液中的滞留提供了有效且灵活的途径。然而, 该策略的效能高度依赖于聚合物材料的理化性质(如分子质量、链柔韧性) 及复杂的生理环境。未来的研究应侧重于对聚合物材料进行更精细的功能化设计, 以优化相互作用的强度与稳定性, 从而推动此类黏附系统向更高效率、可控响应的方向发展。

4.1.3　巯基化策略

巯基化策略的核心是通过在纳米载体表面引入外源性巯基(-SH), 使其能够与胃肠道黏液层中半胱氨酸残基或黏蛋白的活性巯基发生反应自发氧化反应, 形成二硫键(-S-S-), 从而显著增强载体在黏液中的黏附性^{[56, 57]}。尽管二硫键在还原环境中可发生可逆断裂, 但其作为共价键的结合强度远高于氢键、离子相互作用等非共价力, 能够大幅度提高纳米载体在黏液层的滞留能力。

值得注意的是, 胃肠道的酸性环境(较低pH) 可进一步增强巯基化纳米载体的黏附作用。其机制在于酸性条件能够抑制载体自身分子内二硫键的形成, 从而增加纳米载体与黏蛋白形成二硫键的机会^{[41, 58]}。常用的巯基化试剂包括半胱氨酸(cysteine)、巯基乙酸(thioglycolic acid, TGA)、4-硫代丁基脒(4-thiobutylamidine, TBA) 和谷胱甘肽(glutathione) 等。这些试剂可通过化学反应接枝到聚合物(如PAA)、天然多糖(如壳聚糖、海藻酸钠) 或蛋白质等载体材料上。这些材料本身富含羟基、羧基等活性基团, 为巯基的引入提供了理想的反应位点。

研究证实, 巯基化修饰可显著提升纳米载体的黏附性能。例如, Dünnhaupt等^[48]研究表明, 经半胱氨酸修饰的PAA-NPs其黏附性较未修饰组提高了约6倍。Bravo-Osuna等^[49]采用TBA对壳聚糖进行巯基化修饰后, 将其涂覆于聚氰基丙烯酸异丁酯纳米粒表面, 结果显示其与黏液的黏附作用显著增强。

综上, 巯基化策略通过形成牢固的二硫共价键, 为增强纳米载体的黏附性提供了一条高效途径。然而, 该策略的实际应用也面临一些挑战: 一方面, 巯基化聚合物与黏蛋白的半胱氨酸残基之间的二硫键在生理环境下的动态可逆性可能限制黏附的持续时间; 另一方面, 载体表面的巯基在发挥黏附功能前, 可能发生分子内或分子间巯基的相互作用, 导致纳米载体的意外聚集或性质改变^[41]。因此, 未来的研究需致力于优化巯基的密度与空间分布, 以在最大化黏附效能的同时, 维持纳米载体系统的胶体稳定性, 推动该策略向更可靠、更可控的方向发展。

4.2　黏液穿透型策略

区别于黏液黏附型策略, 黏液穿透型策略的核心在于最大限度降低纳米载体与黏液组分之间的非特异性相互作用, 或通过主动破坏黏蛋白网络结构, 减少药物在黏液中的滞留。该策略旨在促使纳米载体快速穿透黏液层, 最终到达深层黏液或直接接触肠上皮细胞表面, 实现高效扩散和药物递送^[59]。该策略主要通过以下两种途径实现: ①表面亲水化/惰性化修饰: 采用亲水性聚合物、两性离子材料或构建电中性表面, 屏蔽与黏蛋白的疏水/静电相互作用; ②黏液溶解策略: 利用黏液溶解剂或蛋白水解酶降解黏蛋白交联网络结构。表2^[60-68]系统总结了相关黏液穿透型纳米递药系统的设计策略及性能特点。

4.2.1　亲水性穿透策略

黏蛋白纤维表面的疏水片段是导致纳米载体滞留的关键因素之一。亲水性穿透策略的核心在于在纳米载体表面构建强亲水性、高度水化的“保护层”, 以有效屏蔽其与黏蛋白疏水域的相互作用, 同时减少与其他黏液组分的非特异性结合。这一修饰能显著降低扩散阻力, 促进载体在黏液网络中的快速渗透。常用于构建亲水化表面的材料包括聚乙二醇(polyethylene glycol, PEG)、聚(2-恶唑啉) [poly(2-oxazoline), POZ] 和聚羟丙甲丙烯酸甲酯(polyhydroxypropyl methacrylate, pHPMA) 等。其中, PEG凭借其优异的亲水性和生物相容性, 已成为最经典且广泛应用的表面修饰材料^[57]。高密度PEG修饰可在纳米粒表面形成紧密的“刷状”结构, 有效阻隔其与黏液成分的非必要相互作用^[69]。

研究表明, PEG的分子质量和表面修饰密度是决定其穿透效率的关键参数。Boylan等^[70]发现, 采用低分子质量(2~5 kDa) PEG修饰的纳米粒可在黏液中快速渗透; 同时, 足够的修饰密度是形成有效空间屏蔽的必要条件。Xu等^[22]系统比较了不同表面密度的PEG-5k修饰纳米粒发现, 结果显示至少需要5%的PEG覆盖率才能有效抑制其与黏蛋白的结合。Yuan等^[60]开发的PEG修饰载多柔比星固体脂质纳米粒, 其在Caco-2/HT29共培养细胞模型和离体肠道组织中均表现出显著增强的黏液穿透能力, 而未修饰的脂质纳米粒则大量滞留于黏液层中; 药代动力学结果进一步证实, PEG修饰组的相对生物利用度较未修饰组提高了1.99倍。

POZ是另一类极具潜力的亲水性材料, 其生物相容性与PEG相当甚至更优, 并表现出更高的体内稳定性^[71]。为优化其亲水性能, Mansfield等^[61]合成了侧链为甲基的聚(2-甲基-2-噁唑啉) [poly(2-methyl-2-oxazoline), PMOZ], 并通过巯基-烯点击反应将其共价修饰到硫醇化二氧化硅纳米粒表面。猪胃黏液穿透实验显示, PMOZ修饰显著增强了纳米粒的渗透能力, 证实了通过提高POZ亲水性来增强穿透效果的可行性。

pHPMA则因其独特的pH响应解离行为而受到广泛关注^[72]。Liu等^[62]将载胰岛素的TMC自组装纳米粒表面修饰pHPMA, 研究结果表明pHPMA的修饰显著增强了纳米粒的黏液穿透能力。更重要的是, pHPMA在穿透黏液层后即开始解离脱落, 暴露出内部的TMC纳米粒核随后通过旁细胞途径进行跨上皮转运, 展现出智能递送的潜力。

尽管以PEG为代表的亲水性穿透策略在增强纳米载体黏液渗透方面展现出显著优势, 但该策略的整体发展仍面临一系列共性挑战。首先, PEG的应用受到潜在的免疫原性(如PEG抗体介导的清除) 及过度修饰可能阻碍细胞摄取等问题的制约^[73]; 其次, POZ等新兴材料虽前景良好, 但目前相关研究仍不够系统深入, 其实际应用潜力尚未充分发掘。而pHPMA等响应型材料则受限于其复杂的制备工艺及体内解离动力学的不可预测性。因此, 未来的研究应致力于开发更安全、更智能的新型亲水性聚合物, 并精细调控其修饰参数, 以实现更加高效和可控的黏液穿透递送。

4.2.2　惰性穿透策略

黏液中富含疏水性片段及带负电荷的基团, 易通过疏水作用和静电吸附捕获纳米载体。惰性穿透策略的核心在于设计兼具高亲水性与电中性表面的纳米载体, 以最大限度地减少其与黏液组分之间的非特异性相互作用。通过避免被黏液网络捕获, 从而促进载体在黏液层中的快速扩散与高效穿透。此类粒子表面通常包覆有致密的惰性(低黏附性) 材料, 可有效屏蔽与黏液成分的作用^[74]。常用的惰性穿透材料包括PEG、普朗尼克F127 (pluronic F-127, F127)、聚多巴胺(polydopamine, PDA) 及两性离子材料等^{[74, 75]}。

Lai等^[76]首次报道PEG凭借其高度亲水性和电中性表面, 能显著减少与黏液组分的相互作用, 从而促进纳米粒子在黏液网络中的快速扩散。这一发现奠定了PEG作为经典黏液穿透材料的地位。Tan等^[63]制备了PEG修饰的载重组生长激素(recombinant growth hormone, RGH) 的复合细胞穿透肽(cell-penetrating peptides, CPPs) 介孔二氧化硅纳米粒(CPP/PEG-LMSN)。体外药效学结果表明, CPP/PEG-LMSN给药组HepG2细胞上清液中的促生长因子水平比RGH溶液组提高了5.41倍。在体内药效学研究中, CPP/PEG-LMSN组大鼠体重增长了4.91%, 而RGH溶液组几乎没有增长, 有力地证明了该策略的有效性。

F127是一种非离子型聚氧乙烯-聚氧丙烯共聚物, 同时具备亲水与疏水链段, 适用于包覆微粒或嵌入脂质体磷脂双层中, 不仅可改善制剂稳定性, 还能增强药物的缓释性能^[77]。Chen等^[64]分别用壳聚糖和F127修饰载难溶性药物环孢素A的脂质体。体内外研究表明, F127修饰的脂质体在胃肠液中表现出更高的稳定性, 与壳聚糖修饰的脂质体相比, 其生物利用度提高了1.84倍。

PDA是通过多巴胺聚合形成的高分子材料, 具有高生物相容性和多功能表面修饰能力。Hu等^[65]制备了PDA修饰的PLGA纳米粒, 并利用琼脂糖凝胶层模型评估其黏液穿透能力。结果显示, PDA修饰后的PLGA纳米粒在凝胶层中表现出优异的黏液穿透能力, 其穿透率(69.6 ± 3.4)%显著高于未经修饰的PLGA纳米粒(37.2 ± 0.7)%。

两性离子化合物是一类具有极强的亲水性和高生物相容性的电中性聚合物。其修饰的纳米载体表面性质与细胞磷脂膜相似, 有助于促进上皮细胞摄取。Veider等^[66]制备了大豆卵磷脂和PEG修饰的水包油型纳米乳液, 并评价其在Caco-2/HT29细胞单层模型的黏液渗透行为和细胞摄取行为。结果表明, 大豆卵磷脂修饰的纳米乳液的黏液渗透性与PEG修饰组相当, 且细胞摄取效率更高。

总体而言, 惰性穿透策略通过构建惰性载体表面, 能有效减少与黏液组分的非特异性相互作用, 为纳米载体高效穿透黏液屏障提供了普适性方案。该策略的主要优势在于设计的明确性和材料的多样性, 例如PEG的经典应用、F127兼具稳定与缓释特性、PDA的多功能修饰能力, 以及两性离子材料在促进细胞摄取方面的独特潜力。然而, 该策略仍面临一些挑战: 部分材料(如PEG) 存在潜在的免疫原性风险; 两性离子材料虽前景广阔, 但其在口服递送中的行为机制研究尚不充分。未来研究需在深化材料生物学效应基础上, 优化其表面修饰策略, 实现黏液穿透与细胞递送的高效协同。

4.2.3　黏液溶解策略

与上述通过表面亲水性或惰性材料修饰纳米载体以减弱相互作用的穿透策略不同, 该策略旨在主动降解黏液的结构完整性, 降低其黏弹性和致密度, 从而促进纳米载体的扩散和渗透。该策略主要包括裂解二硫键和水解黏蛋白两类方法^[41]。

二硫键是维持黏液网络机械强度和黏弹性能的关键化学键, 破坏二硫键可显著降低黏液黏度, 削弱其对纳米载体的截留能力。常用的二硫键断裂剂包括N-乙酰半胱氨酸、N-十二烷基-4-巯基丁酰胺和2-巯基-N-辛基乙酰胺等^{[77, 78]}。这些试剂可与药物共载于纳米载体中, 在穿越黏液过程中缓慢释放, 实现对局部黏液网络的选择性破坏。

另一方面, 水解黏蛋白主要是通过蛋白水解酶水解黏蛋白骨架的多肽链, 进而破坏其网络结构。常用蛋白水解酶包括胰蛋白酶(trypsin) 木瓜蛋白酶(papain, PAP) 和菠萝蛋白酶(bromelain, BROM) 等^[79]。Shahzadi等^[67]制备了trypsin修饰的自乳化药物递送系统(self-emulsifying drug delivery system, SEDDS), 并采用猪肠黏液评估其黏液渗透特性。结果显示, 酶修饰SEDDS的黏液穿透性较未修饰组提高了2.6倍。Leichner等^[68]制备了PAP修饰的SEDDS, 通过旋转硅胶管实验与Transwell扩散模型均证实, 其黏液渗透能力显著优于未经酶修饰的对照组。

黏液溶解策略通过主动解构黏液层的结构完整性, 为增强纳米载体渗透提供了一种独特且高效的路径。其主要优势在于能够直接、显著地降低黏液黏弹性, 从而极大地提升药物载体的跨屏障转运效率。然而, 其应用仍面临多重的局限性: 首先, 目前基于二硫键裂解策略的相关研究报道较少, 其方法研究尚不充分, 技术成熟度低; 其次, 蛋白水解酶修饰纳米载体的构建技术仍处于起步阶段, 可供选择的载体材料有限, 且酶活性在储存与递送过程中易失活降解, 严重影响体系稳定性。更关键的是, 该策略可能破坏正常黏液的生理屏障功能, 造成局部组织损伤, 削弱其对病毒等外来物质的防御能力, 从而增加感染风险。因此该策略适用场景可能仅限于病理条件下黏液异常增厚的疾病(如炎症性肠病、功能性肠道紊乱等)。未来的研究应在保障安全性的前提下, 致力于进一步优化酶或裂解剂的控释特性与靶向能力, 以推动该策略的临床转化。

4.3　智能与协同递送策略

除了经典的黏附型和穿透型策略, 研究者们正致力于开发更为复杂和智能化的新型递送系统, 以协同克服多重生理屏障。这些先进策略通常整合多种作用机制, 主要包括黏液黏附与穿透结合型、zeta电位转变型、特异性结合型及仿生功能化等。

4.3.1　黏液黏附与穿透结合型策略

该策略旨在构建可响应环境或时间因素动态调整表面性质的“智能”载体, 实现从初始黏附到后续穿透的动态转换。Hauptstein等^[80]开发的PEG-硫醇化壳聚糖(Chito-PEG-SH) 是典型代表。①黏附阶段: 载体表面的硫醇基(-SH) 与黏蛋白的巯基形成二硫键, 产生强黏附力, 延长肠道滞留时间; ②穿透阶段: 随着时间的推移或环境变化(如pH、还原环境), 二硫键逐渐断裂; 同时外层的PEG链发挥亲水性屏蔽作用, 减少与黏蛋白的非特异性相互作用, 促进载体释放并穿透剩余黏液层。实验表明, 与单一壳聚糖相比, Chito-PEG-SH不仅初始黏附性更强, 其在大鼠肠黏液模型中的整体穿透能力也显著提高了2.7倍, 展现出动态转换策略的显著优势。

Liu等^[81]开发了一种基于壳聚糖-巯基乙酸-Pluronic F127 (CS-TGA-PF) 的脂质体系统用于紫杉醇的口服递送。黏蛋白黏附定量评估结果显示, CS-TGA-PF脂质体的黏蛋白黏附量比单一CS包覆的脂质体提高了3倍。体内肠道分布研究显示, 大鼠口服香豆素-6标记的CS-TGA-PF脂质体后, 不仅在肠道表面观察到更强的荧光信号, 荧光还可深入分布于绒毛内部, 表明该系统兼具优异的黏液黏附与渗透能力。这些结果证实CS-TGA-PF脂质体是一种具有潜力的紫杉醇口服纳米递送系统。

黏液黏附与穿透结合型策略通过时序性或环境响应性的设计, 巧妙地协同了“黏附”与“穿透”两个看似矛盾的关键特性, 成功突破了传统单一策略的局限。相较于仅注重黏附(易被快速清除) 或仅注重穿透(滞留时间不足) 的传统载体, 该策略不仅显著延长了药物在吸收部位的停留, 还确保了其后续的高效跨屏障转运, 从而整体上提升了药物的口服递送效率。此外, 其设计理念为共载不同理化性质的药物提供了可能性, 展现了极高的灵活性与应用潜力。未来, 通过引入更精准的响应机制与更高效的功能材料, 此类智能递送系统有望为复杂口服给药挑战提供全新的解决方案。

4.3.2　Zeta电位转变型策略

该策略以肠道(尤其小肠刷状缘) 高表达的碱性磷酸酶(alkaline phosphatase, ALP) 作为生物触发器, 设计“核-壳”结构: ①初始状态(带负电, 利于穿透): 带正电内核(如壳聚糖) 被带负电的“保护基团”(如磷酸根基团) 屏蔽, 使整体表面电荷为负值。这种负电荷或电荷中性表面有利于减少与带负电黏蛋白的静电排斥/吸引, 促进在黏液层中的初始穿透; ②酶触发反转(带正电, 促进吸收): 当载体到达富含ALP的小肠区域时, ALP特异性水解掉外层的磷酸根基团, 暴露出带正电的内核。暴露的正电荷可增强载体与带负电的肠上皮细胞膜的静电相互作用, 促进细胞摄取或旁细胞转运, 从而提高药物吸收。Le-Vinh等^[82]制备了一种磷酸化的壳聚糖胶束, 其壳聚糖阳离子核心被磷酸盐掩盖为负电荷, 在初始阶段展现出优异的黏液渗透性, 与未经修饰的壳聚糖胶束相比提高了约6倍。到达小肠后, ALP触发脱磷酸化, 电荷反转为正, 有效促进了后续的细胞摄取。

目前, CPPs常被用于增强药物的跨膜转运, 但其阳离子特性易导致与黏液之间相互作用, 反而限制其穿透效率。为克服这一局限, 研究者们常将CPPs与聚磷酸盐(polyphosphate, PP) 结合, 构建电荷转变的递送系统。例如, Knoll等^[83]开发了一种载沙奎那韦的聚阳离子CPPs (R9SA) 修饰的纳米结构脂质载体(nanostructured lipid carriers, NLCs), 并在其表面包覆PP, 将其掩盖为负电荷表面。研究显示, PP-R9SA-NLCs表现出显著高于R9SA-NLCs的黏液渗透能力, 且其细胞摄取量也增加了13.2倍。类似地, Truszkowska等^[84]制备了油酰-低聚赖氨酸修饰的脂质体, 并在其表面涂覆PP。在猪肠黏液体外模型中, PP-脂质体的黏液渗透性在6 h内较未修饰组提高了约12倍, 同时在Caco-2细胞中表现出良好的细胞摄取能力。

Zeta电位转变型策略通过构建酶响应性电荷反转系统, 实现了药物载体在黏液层高效穿透与细胞表面有效摄取的有效协同, 展现出显著优于传统单一电荷策略的递送效率。该策略的核心优势在于其动态调控能力: 载体初始的负电荷表面最大限度地保障了其在黏液中的快速扩散; 而到达吸收部位后, 在ALP触发下迅速恢复正电性, 从而强力促进细胞膜相互作用及后续内化或旁细胞转运。现有研究已从黏液渗透性、细胞摄取及整体生物利用度等多个层面验证了该策略的可行性与优越性。随着对酶响应动力学及载体构建技术的深入研究, 该类智能递送系统有望为口服药物的高效递送开辟新路径。

4.3.3　受体介导的特异性靶向策略

受体介导的特异性靶向策略通过修饰可与肠道特定受体(位于上皮细胞或黏液组分) 高亲和力结合的配体, 实现主动靶向递送。常用的配体包括凝集素(lectin)、维生素B12等。

Lectin可特异性识别并结合肠上皮细胞表面或黏蛋白上特定糖基化受体, 这种特异性结合能显著增强载体在胃肠道靶部位的黏附滞留^[85]。Singh等^[86]开发了一种由刀豆球蛋白A凝集素(concanavalin A, ConA) 修饰的载有阿普斯特(apremilast, Apr) 的脂质纳米载体(ConA-Apr-LNCs)。细胞摄取研究表明, 通过凝集素介导的主动靶向作用, ConA-Apr-LNCs的细胞摄取能力较未修饰组显著增强。在关节炎大鼠模型体内药效学研究中, ConA-Apr-LNCs治疗组显示出最轻微的骨侵蚀和最优的关节保护作用。Abdel-Azeem等^[87]制备了载替格瑞洛的凝集素修饰的脂质纳米载体(C-TLN), 用于靶向血小板糖蛋白受体以治疗急性冠脉综合征。研究结果表明, C-TLN对凝血酶激活血小板的结合率超过50%, 显著高于未修饰TLN (< 15%)。药代动力学研究表明, C-TLN的口服相对生物利用度较游离替格瑞洛提高了2.37倍。

维生素B12是一种由微生物合成的含钴维生素, 它能被回肠上皮细胞上的蛋白内因子受体(intrinsic factor, IF) 特异性识别, 从而介导吸收^[88]。Chalasani等^[89]将维生素B12与载胰岛素的葡聚糖纳米颗粒偶联, 成功利用IF受体途径, 显著改善了胰岛素在糖尿病大鼠模型中的口服递送效率。

受体介导的特异性靶向策略通过配体-受体间的特异性识别, 实现了纳米载体在肠道部位的精准定位与高效靶向。相较于传统的非特异性黏附的递送系统, 该策略具有显著优势: ①借助配体与相应受体的高亲和力结合, 可显著增强载体在目标部位(如特定肠段或黏液组分) 的滞留与富集; ②通过主动靶向机制提升细胞摄取效率, 从而促进药物的跨上皮转运; ③在改善口服生物利用度的同时, 有助于提高治疗特异性。尽管其在配体稳定性、免疫原性及规模化制备等方面仍存在挑战, 但该策略无疑为开发下一代高效、低毒的口服靶向递药系统提供了重要方向。

4.3.4　受生物启发的仿生功能化策略

受生物启发的仿生功能化策略借鉴自然界中生物系统(如病毒、细菌、外泌体等) 穿越生物屏障的独特机制, 旨在设计具有优异递送性能的仿生纳米载体。病毒衣壳表面通常具有亲水性、电中性及特定的纳米拓扑结构(如光滑、密集排列的蛋白亚基), 这些特性使其能有效实现快速黏液穿透^[90]。Zhang等^[91]设计了一种表面功能化介孔二氧化硅纳米粒(MSN-NH2@COOH/CPP5), 通过模拟病毒表面特性, 实验证明其能高效穿透黏液层并促进跨肠上皮转运。该载体负载胰岛素后, 在糖尿病大鼠模型中血糖降幅近50%。Sang等^[92]开发了一种具有病毒仿生表面拓扑结构的介孔二氧化硅纳米粒(chiral virus-like nanospikes, CVSN)。CVSN在黏液渗透和细胞摄取方面均表现出显著优势: 在大鼠肠黏液中, CVSN的渗透率达到23.19%, 显著优于未修饰的平滑固体纳米粒(11.58%), 同时其在Caco-2细胞中的摄取能力也显著增强。

外泌体是一种天然的内源性纳米囊泡, 可介导细胞间生物信息传递, 并具备向特定组织或细胞递送治疗分子的潜力^[93]。作为一种天然的脂质纳米载体, 外泌体在靶向药物递送领域展现出广阔前景。Wu等^[94]制备了载胰岛素的牛奶源性外泌体(EXO@INS)。研究显示, EXO@INS在Ⅰ型糖尿病大鼠中表现出优于皮下注射胰岛素的降血糖效果, 其相对生物利用度较游离胰岛素提高了10.6倍。此外, 该系统在胃肠道环境中表现出良好的稳定性与对肠道细胞的高亲和力。

某些微生物代谢物具有调节黏液性质或上皮屏障功能。Wu等^[95]将微生物代谢产物丁酸修饰在负载胰岛素的PEG纳米粒表面, 与未经修饰的PEG纳米粒相比, 丁酸修饰的纳米粒的口服生物利用度提高了2.87倍。同时, 细菌孢子具有极强的环境耐受性和穿透能力。Song等^[96]开发了一种负载多柔比星和索拉非尼的仿生孢子纳米颗粒, 该系统能显著改善黏液渗透, 有效克服多种生理屏障, 并提高治疗效果。

受生物启发的仿生策略通过模拟生物体的结构功能一体化特性, 为口服药物递送提供了创新且高效的途径。该策略的核心优势在于: 模拟病毒表面特性增强黏液穿透; 利用外泌体的天然靶向性提升大分子递送效率; 借鉴微生物机制改善组织渗透。这些仿生设计实现了“穿透-靶向-吸收”等多重递送环节的有效协同, 展现出在口服给药中的突出应用潜力。随着对生物系统作用机制的深入解析与仿生构建技术的不断进步, 该策略有望为口服纳米药物的临床转化开辟新的途径。

5　展望与挑战

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胃肠道黏液屏障作为口服药物递送的关键生理障碍之一, 严重制约了许多药物的口服生物利用度。系统解析其结构与屏障机制, 对于设计高效递送系统具有重要研究意义。本文系统综述了胃肠道黏液屏障的组成结构、理化性质及其屏障特性, 阐明该屏障影响药物口服吸收的作用机制, 并系统梳理了当前克服该屏障的多种纳米递送策略, 从经典的黏附、穿透策略到新型的黏附与穿透结合、酶响应、受体介导的特异性靶向及仿生功能化策略等。这些策略在提升药物口服生物利用度方面展现出良好潜力。随着多学科深度融合发展, 更多智能化纳米递药系统被开发出来, 为药物口服递送提供了新思路。

然而, 包括蛋白质、多肽类等大分子药物的口服吸收仍面临严峻挑战。其生物利用度低下的问题, 主要由以下两方面因素协同作用所致: 一方面是这类药物自身具有分子质量大、结构稳定性差和膜渗透性差等固有特性; 另一方面在于胃肠道黏液屏障的阻碍, 黏液致密网状结构对其产生显著的尺寸和扩散限制。同时, 胃肠道复杂的酶环境诱导药物快速失活。这些因素共同作用, 导致此类药物的口服生物利用度极低。例如, 已上市的口服肽类药物如索马鲁肽的生物利用度仅约0.5%~1%^[97]; 胰岛素作为典型的亲水性多肽大分子, 口服递送更具挑战性, 现有研究中其口服生物利用度的提升效果大多仍难以突破20%^[98]。

此外, 这些口服递送策略在临床转化层面也面临多重共性挑战: 首先, 在材料安全性方面, 广泛使用的PEG化策略虽能有效增强穿透性, 但其潜在的免疫原性风险可能加速引发抗体介导的血液清除效应, 影响长期疗效; 其次, 在屏障安全性方面, 黏液溶解策略虽能显著提升穿透效率, 却可能破坏黏液的生理屏障功能, 增加肠道感染风险。因此, 其应用应严格限于病理状态下黏液异常增厚的疾病。此外, 在系统整合性和可控性方面, 多数现有策略仍侧重于单一功能的实现, 难以协同应对胃肠道中复杂的多重屏障环境; 而多功能集成系统又常面临制备工艺复杂、体内行为不可控及规模化生产困难等瓶颈。

综上所述, 尽管口服纳米递送系统在克服黏液屏障方面已取得显著进展, 但其在走向临床转化的应用过程中仍存在诸多挑战。未来研究应聚焦于以下关键方向: 一是开发更安全、智能的新型递送材料, 并系统评估其长期毒性、免疫原性及体内代谢行为等; 二是构建多功能时序协同系统, 借鉴黏附-穿透结合型策略的理念, 融合黏附、穿透与细胞摄取环节, 实现程序化递送; 三是建立更具预测性的评价体系, 结合类器官、肠道芯片等先进模型与成像技术, 构建更加贴近人体真实生理屏障的实验模型与分析技术, 体外/离体模型与先进表征技术, 以提升实验数据的预测价值与临床转化价值。通过多学科协同创新, 相信在未来有望推动更多智能、精准、多功能集成的口服纳米递药系统实现临床突破。

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2026年第61卷第4期

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doi: 10.16438/j.0513-4870.2025-1034

接收时间：2025-09-01
首发时间：2026-09-21
出版时间：2026-04-12

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收稿日期：2025-09-01
修回日期：2025-10-09

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江西中医药大学, 现代中药制剂教育部重点实验室, 江西南昌 330004

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陈颖翀, E-mail: yc_chen1020@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Adhesion strategy	Drug/nano-formulation	Material	Advantage	Ref.
Electrostatic incorporation	Vinorelbine; liposomes	Chitosan	Improved bioavailability by 2.1-fold compared to the vinorelbine solution	[42]
	Insulin; nanoparticles	Chitosan; PLGA	Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration	[43]
	Gefitinib; nanoparticles	CMC; F68; PLGA	Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group	[44]
Bonding force adhesion	Calcitonin; nanoparticles	PAA	Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin	[45]
	Acetaminophen; nanoparticles	Chitosan; PLGA	Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight	[46]
	Sitagliptin; nanoparticles	HPMC; PLGA	Prolonged adhesion duration and enhanced mucoadhesion	[47]
Thiolation strategy	-; nanoparticles	PAA; cysteine	Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group	[48]
	-; nanoparticles	Chitosan; TBA	Significantly enhanced mucoadhesive property of PIBCA-NPs	[49]

Adhesion strategy

Drug/nano-formulation

Material

Advantage

Ref.

Electrostatic incorporation

Vinorelbine; liposomes

Chitosan

Improved bioavailability by 2.1-fold compared to the vinorelbine solution

[42]

Insulin; nanoparticles

Chitosan; PLGA

Excellent bioadhesion with a strong fluorescence signal still observed in the intestinal tract 8 hours after oral administration

[43]

Gefitinib; nanoparticles

CMC; F68; PLGA

Higher adhesion in the small intestine, and improved bioavailability by approximately 1.6-fold compared to the unmodified group

[44]

Bonding force adhesion

Calcitonin; nanoparticles

PAA

Significantly enhanced mucoadhesion compared with calcitonin solution, and effectively improved oral absorption of calcitonin

[45]

Acetaminophen; nanoparticles

Chitosan; PLGA

Significantly enhanced mucoadhesive property, which was further improved with increasing chitosan concentration and molecular weight

[46]

Sitagliptin; nanoparticles

HPMC; PLGA

Prolonged adhesion duration and enhanced mucoadhesion

[47]

Thiolation strategy

-; nanoparticles

PAA; cysteine

Enhanced mucoadhesion by approximately 6-fold compared to the unmodified group

[48]

-; nanoparticles

Chitosan; TBA

Significantly enhanced mucoadhesive property of PIBCA-NPs

[49]

Penetration strategy	Drug/nano-formulation	Material	Advantage	Ref.
Hydrophilic penetration	DOX; SLNs	PEG	Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group	[60]
	-; silica nanoparticles	PMOZ	Significantly enhanced mucus-penetrating capability of silica nanoparticles	[61]
	Insulin; nanoparticles	pHPMA; TMC	Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles	[62]
Inert penetration	RGH; mesoporous silica nanoparticles	PEG; CPPs	Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies	[63]
	CyA; liposomes	F127	Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes	[64]
	-; nanoparticles	PDA; PLGA	Faster mucus penetration ability compared with unmodified PLGA nanoparticles	[65]
	-; nanoemulsions	Soy lecithin	Comparable mucus permeability to the PEG-modified group, and higher cell uptake	[66]
Mucolytic penetration	-; SEDDS	Trypsin	Increased mucus permeability by 2.6-fold compared with unmodified SEDDS	[67]
	-; SEDDS	PAP	Significantly superior mucus-penetrating capability compared to the enzyme-unmodified SEDDS	[68]

Penetration strategy

Drug/nano-formulation

Material

Advantage

Ref.

Hydrophilic penetration

DOX; SLNs

PEG

Significantly enhanced mucus-penetrating capability, and improved relative bioavailability by 1.99-fold compared to the unmodified group

[60]

-; silica nanoparticles

PMOZ

Significantly enhanced mucus-penetrating capability of silica nanoparticles

[61]

Insulin; nanoparticles

pHPMA; TMC

Enhanced mucus-penetrating capability of TMC self-assembled nanoparticles

[62]

Inert penetration

RGH; mesoporous silica nanoparticles

PEG; CPPs

Higher growth-promoting factors level by 5.41-fold compared with the RGH solution group in vitro cells studies, and increased (4.91%) body weight in rats in vivo efficacy studies

[63]

CyA; liposomes

F127

Enhanced stability in gastrointestinal fluids and improved bioavailability by 1.84-fold compared to chitosan-modified liposomes

[64]

-; nanoparticles

PDA; PLGA

Faster mucus penetration ability compared with unmodified PLGA nanoparticles

[65]

-; nanoemulsions

Soy lecithin

Comparable mucus permeability to the PEG-modified group, and higher cell uptake