The capability of cell-penetrating peptides (CPPs) to enable translocation of cargos across biological barriers shows promising pharmaceutical potential for the transport of drug molecules, as well as nanomaterials, into cells. Herein, we report on the optimization of a CPP, namely sC18, in terms of its translocation efficiency and investigate new CPPs regarding their interaction with silica nanoparticles (NPs). First, alanine scanning of sC18 yielded 16 cationic peptides from which two were selected for further studies. Whereas in the first case, a higher positive net charge and enhanced amphipathicity resulted in significantly higher internalization rates than sC18, the second one demonstrated reduced cellular uptake efficiencies and served as a control. We then attached these CPPs to silica nanoparticles of different sizes (50, 150 and 300 nm) via electrostatic interactions and could demonstrate that the secondary alpha-helical structure of the peptides was preserved. Following this, cellular uptake studies using HeLa cells showed that the tested CPP-NPs were successfully translocated into HeLa cells in a size-dependent manner. Moreover, depending on the CPP used, we realized differences in translocation efficiency, which were similar to what we had observed for the free peptides. All in all, we highlight the high potential of sequential fine-tuning of CPPs and provide novel insights into their interplay with inorganic biologically benign nanoparticles. Given the high cellular permeability of CPPs and their ability to translocate into a wide spectrum of cell types, our studies may stimulate future research of CPPs with inorganic nanocarrier surfaces.
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