Arginine Surface Density of Nanoparticles Controls Nonendocytic Cell Uptake and Autophagy Induction

Nonendocytic cell uptake of nanomaterials is challenging, which requires specific surface chemistry and smaller particle size. Earlier works have shown that an arginine-terminated nanoparticle of <10-20 nm size shows nonendocytic uptake via direct membrane penetration. However, the roles of surface arginine density and the arginine-arginine distance at the nanoparticle surface in controlling such nonendocytic uptake mechanism is not yet explored. Here we show that a higher arginine density at the nanoparticle surface with an arginine-arginine distance of <3 nm is the most critical aspect for such nonendocytic uptake. We have used quantum dot (QD)-based nanoparticles as a model for fluorescent tracking inside cells and for quantitative estimation of cellular uptake. We found that arginine-terminated nanoparticles of 10 nm size can opt for the energy-dependent endocytosis pathway if the arginine-arginine distance is >3 nm. In contrast, nanoparticles with <3 nm arginine-arginine distance rapidly enter into the cell via the nonendocytic approach, are freely available in the cytosol in large amounts to capture the cellular adenosine triphosphate (ATP), generate oxidative stress, and induce ATP-deficient cellular autophagy. This work shows that arginine-arginine distance at the nanoparticle surface is another fundamental parameter, along with the particle size, for the nonendocytic cell uptake of foreign materials and to control intracellular activity. This approach may be utilized in designing nanoprobes and nanocarriers with more efficient biomedical performances.