Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, 1085 Budapest, Hungary.
Cells. 2023 Jun 23;12(13):1700. doi: 10.3390/cells12131700.
Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos. Coupling biologically and medically relevant cargos to CPPs holds great promise of delivering membrane-impermeable drugs into cells. If the cargo is able to interact with certain cell types, uptake of the CPP-drug complex can be tailored to be cell-type-specific. Besides outlining the major membrane penetration pathways of CPPs, this review is aimed at deciphering how properties of the membrane influence the uptake mechanisms of CPPs. By summarizing an extensive body of experimental evidence, we argue that a more ordered, less flexible membrane structure, often present in the very diseases planned to be treated with CPPs, decreases their cellular uptake. These correlations are not only relevant for understanding the cellular biology of CPPs, but also for rationally improving their value in translational or clinical applications.
每本细胞生物学教材都教导我们，质膜的主要作用是将细胞与其周围环境分隔开来，以允许细胞内空间有一个受控的组成。细胞膜的疏水性使得大多数大于 1 kDa 的亲水分子无法穿透。另一方面，细胞穿透肽（CPPs）能够在不破坏膜完整性的情况下穿透这个屏障，它们可以自行穿透，也可以与货物一起穿透。将生物和医学上相关的货物与 CPPs 结合在一起，有望将膜不可渗透的药物递送到细胞内。如果货物能够与某些细胞类型相互作用，那么 CPP-药物复合物的摄取可以被定制为细胞类型特异性。除了概述 CPP 的主要膜穿透途径外，本综述旨在破译膜的特性如何影响 CPP 的摄取机制。通过总结大量的实验证据，我们认为更有序、更不灵活的膜结构，通常存在于计划用 CPP 治疗的疾病中，会降低 CPP 的细胞摄取。这些相关性不仅与理解 CPP 的细胞生物学有关，而且对于合理提高它们在转化或临床应用中的价值也很重要。
