Effects of surface charge and particle size of cell-penetrating peptide/nanoparticle complexes on cellular internalization.

Cell membranes are natural barriers that prevent macromolecules from permeating cells. The efficiency of exogenous materials entering cells relies on various strategies and factors. Cell-penetrating peptides (CPPs) are distinctive molecules that can penetrate cells by themselves, as well as carry cargoes into cells in both covalent and noncovalent manners. In this chapter, we use CPP-mediated delivery of nanomaterials to illustrate the importance of surface charge and size of nanoparticles on cellular uptake. We found that three different arginine-rich CPPs (SR9, HR9, and PR9) are able to form stable complexes with nanomaterials, including quantum dots (QDs) and DNAs, and the complexes can effectively internalize into cells. Our study demonstrated that zetapotential of CPP/cargo nanoparticulate complexes is a key predictor of transduction efficiency. On a different note, a combination of CPPs with cargoes resulted in complexes with various sizes. The most positively charged HR9/cargo complexes displayed the highest protein transduction efficiency. The correlation coefficient analysis demonstrated a high correlation between zeta-potential and transduction efficiency of CPP/DNA complexes. A logarithmic curve was plotted with zeta value against transduction efficiency with an R-squared value of 0.9454. With similar surface charges, particle sizes could affect cellular uptake efficiency of CPP/QD complexes. Collectively, our findings elucidate that zeta-potential of CPP/cargo nanoparticulate complexes plays a major role in determining transduction efficiency, while particle sizes of CPP/ cargo nanoparticulate complexes have a minor effect in cell permeability.