The oral administration of therapeutic peptides and proteins is favoured from a patient and commercial point of view. In order to reach the systemic circulation after oral administration, these drugs have to overcome numerous barriers including the enzymatic, sulfhydryl, mucus and epithelial barrier. The development of oral formulations for therapeutic peptides and proteins is therefore necessary. Among the most promising formulation approaches are lipid-based nanocarriers such as oil-in-water nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes and micelles. As the lipophilic character of therapeutic peptides and proteins can be tremendously increased such as by the formation of hydrophobic ion pairs (HIP) with hydrophobic counter ions, they can be incorporated in the lipophilic phase of these carriers. Since gastrointestinal (GI) peptidases as well as sulfhydryl compounds such as glutathione and dietary proteins are too hydrophilic to enter the lipophilic phase of these carriers, the incorporated therapeutic peptide or protein is protected towards enzymatic degradation as well as unintended thiol/disulfide exchange reactions. Stability of lipid-based nanocarriers towards lipases can be provided by the use to excipients that are not or just poorly degraded by these enzymes. Nanocarriers with a size <200 nm and a mucoinert surface such as PEG or zwitterionic surfaces exhibit high mucus permeating properties. Having reached the underlying absorption membrane, lipid-based nanocarriers enable paracellular and lymphatic drug uptake, induce endocytosis and transcytosis or simply fuse with the cell membrane releasing their payload into the systemic circulation. Numerous in vivo studies provide evidence for the potential of these delivery systems. Within this review we provide an overview about the different barriers for oral peptide and protein delivery, highlight the progress made on lipid-based nanocarriers in order to overcome them and discuss strengths and weaknesses of these delivery systems in comparison to other technologies.

从患者和商业角度来看，治疗性肽和蛋白质的口服给药是有利的。为了在口服给药后到达全身循环，这些药物必须克服许多障碍，包括酶、巯基、粘液和上皮屏障。因此，有必要开发治疗性肽和蛋白质的口服制剂。最有前途的制剂方法包括基于脂质的纳米载体，例如水包油纳米乳液、自乳化药物递送系统 (SEDDS)、固体脂质纳米颗粒 (SLN)、纳米结构脂质载体 (NLC)、脂质体和胶束。由于治疗性肽和蛋白质的亲脂性可以大大增加，例如通过与疏水性抗衡离子形成疏水性离子对 (HIP)，它们可以掺入这些载体的亲脂相中。由于胃肠 (GI) 肽酶以及巯基化合物（例如谷胱甘肽和膳食蛋白质）的亲水性太强而无法进入这些载体的亲脂相，因此可以保护掺入的治疗性肽或蛋白质免受酶促降解以及意外的硫醇/二硫化物交换反应。脂质基纳米载体对脂肪酶的稳定性可以通过使用不被这些酶降解或只是降解不良的赋形剂来提供。尺寸 <200 nm 和粘液惰性表面（如 PEG 或两性离子表面）的纳米载体表现出高粘液渗透特性。到达下面的吸收膜后，基于脂质的纳米载体能够吸收细胞旁和淋巴药物，诱导内吞作用和转胞吞作用或简单地与细胞膜融合，将其有效载荷释放到体循环中。很多的体内研究为这些递送系统的潜力提供了证据。在这篇综述中，我们概述了口服肽和蛋白质递送的不同障碍，强调了基于脂质的纳米载体所取得的进展，以克服这些障碍，并讨论了这些递送系统与其他技术相比的优缺点。