Yang Su, Dong He
Department of Chemistry and Biochemistry, The University of Texas at Arlington Arlington TX 76019 USA
RSC Adv. 2020 Aug 10;10(49):29469-29474. doi: 10.1039/d0ra04748a. eCollection 2020 Aug 5.
The discovery of cell penetrating peptides (CPPs) with unique membrane activity has inspired the design and synthesis of a variety of cell penetrating macromolecules, which offer tremendous opportunity and promise for intracellular delivery of a variety of imaging probes and therapeutics. While cell penetrating macromolecules can be designed and synthesized to have equivalent or even superior cell penetrating activity compared with natural CPPs, most of them suffer from moderate to severe cytotoxicity. Inspired by recent advances in peptide self-assembly and cell penetrating macromolecules, in this work, we demonstrated a new class of peptide assemblies with intrinsic cell penetrating activity and excellent cytocompatibility. Supramolecular assemblies were formed through the self-assembly of designed multidomain peptides (MDPs) with a general sequence of K (QW)E in which the numbers of lysine and glutamic acid can be varied to control supramolecular assembly, morphology and cell penetrating activity. Both supramolecular spherical particles and nanofibers exhibit much higher cell penetrating activity than monomeric MDPs while supramolecular nanofibers were found to further enhance the cell penetrating activity of MDPs. cell uptake results suggested that the supramolecular cell penetrating nanofibers undergo macropinocytosis-mediated internalization and they are capable of escaping from the lysosome to reach the cytoplasm, which highlights their great potential as highly effective intracellular therapeutic delivery vehicles and imaging probes.
具有独特膜活性的细胞穿透肽（CPPs）的发现激发了多种细胞穿透性大分子的设计与合成，这为多种成像探针和治疗药物的细胞内递送提供了巨大机遇和前景。虽然可以设计和合成与天然CPPs相比具有同等甚至更高细胞穿透活性的细胞穿透性大分子，但它们中的大多数都存在中度至重度的细胞毒性。受肽自组装和细胞穿透性大分子领域近期进展的启发，在本研究中，我们展示了一类具有内在细胞穿透活性和优异细胞相容性的新型肽组装体。超分子组装体通过设计的多结构域肽（MDPs）自组装形成，其通用序列为K (QW)E ，其中赖氨酸和谷氨酸的数量可以变化以控制超分子组装、形态和细胞穿透活性。超分子球形颗粒和纳米纤维均表现出比单体MDPs更高的细胞穿透活性，同时发现超分子纳米纤维进一步增强了MDPs的细胞穿透活性。细胞摄取结果表明，超分子细胞穿透纳米纤维通过巨胞饮作用介导内化，并且它们能够从溶酶体逃逸到细胞质中，这突出了它们作为高效细胞内治疗递送载体和成像探针的巨大潜力。
