Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Str. 56, Münster, 48149, Germany.
Center for Soft Nanoscience and Organic Chemistry Institute, University of Muenster, Busso Peus Straße 10, Münster, 48149, Germany.
Adv Sci (Weinh). 2021 Sep;8(18):e2100694. doi: 10.1002/advs.202100694. Epub 2021 Jul 18.
The transport of membrane impermeable compounds into cells is a prerequisite for the efficient cellular delivery of hydrophilic and amphiphilic compounds and drugs. Transport into the cell's cytosolic compartment should ideally be controllable and it should involve biologically compatible and degradable vehicles. Addressing these challenges, nanocontainers based on cyclodextrin amphiphiles that are stabilized by a biodegradable peptide shell are developed and their potential to deliver fluorescently labeled cargo into human cells is analyzed. Host-guest mediated self-assembly of a thiol-containing short peptide or a cystamine-cross-linked polypeptide shell on cyclodextrin vesicles produce short peptide-shelled (SPSV ) or polypeptide-shelled vesicles (PPSV ), respectively, with redox-responsive and biodegradable features. Whereas SPSV are permeable and less stable, PPSV effectively encapsulate cargo and show a strictly regulated release of membrane impermeable cargo triggered by either reducing conditions or peptidase treatment. Live cell experiments reveal that the novel PPSV are readily internalized by primary human endothelial cells (human umbilical vein endothelial cells) and cervical cancer cells and that the reductive microenvironment of the cells' endosomes trigger release of the hydrophilic cargo into the cytosol. Thus, PPSV represent a highly efficient, biodegradable, and tunable system for overcoming the plasma membrane as a natural barrier for membrane-impermeable cargo.
将不透膜的化合物运送到细胞内是将亲水性和两亲性化合物和药物有效递送到细胞内的前提条件。进入细胞胞质腔的运输在理想情况下应该是可控的，并且应该涉及生物相容和可降解的载体。为了应对这些挑战，开发了基于环糊精两亲物的纳米容器，该容器由可生物降解的肽壳稳定，并分析了它们将荧光标记的货物递送到人细胞中的潜力。含有巯基的短肽或半胱胺交联的多肽壳在环糊精囊泡上通过主体-客体介导的自组装，分别产生短肽壳（SPSV）或多肽壳囊泡（PPSV），具有氧化还原响应和可生物降解的特性。虽然 SPSV 是可渗透的且不太稳定，但 PPSV 可以有效地封装货物，并在还原条件或肽酶处理下严格调节对膜不透性货物的释放。活细胞实验表明，新型 PPSV 容易被原代人内皮细胞（人脐静脉内皮细胞）和宫颈癌细胞内化，并且细胞内体的还原微环境会触发亲水性货物释放到细胞质中。因此，PPSV 代表了一种高效、可生物降解和可调节的系统，可克服作为膜不透性货物天然屏障的质膜。
