Surface Charge of Nanoparticles Determines Their Endocytic and Transcytotic Pathway in Polarized MDCK Cells

TLDR

Drug delivery to polarized epithelial organs is limited by the mucosal barrier and low apical endocytosis rates. We investigated how nanoparticle surface charge influences apical membrane entry and intracellular trafficking. We examined cationic and anionic nanoparticles in polarized MDCK cells to assess their uptake pathways. Both cationic and anionic nanoparticles predominantly use clathrin‑mediated endocytosis, with a macropinocytosis fraction, and a substantial portion transcytoses to the basolateral membrane; anionic particles also enter lysosomes, whereas cationic particles show potential for delivering drugs across epithelia to the bloodstream.

Abstract

A major challenge in drug delivery is the internalization through the apical plasma membrane of the polarized epithelial cells lining organs facing the external environment, e.g., lungs and the gastrointestinal tract. The reduced permeation of drugs entering through this pathway is in part due to the mucosal barrier and low rate of endocytosis at these membranes. We investigated the possible role of nanoparticle surface charge on its entry through the apical plasma membrane and its intracellular pathway. We found that both cationic and anionic nanoparticles are targeted mainly to the clathrin endocytic machinery. A fraction of both nanoparticle formulations is suspected to internalize through a macropinocytosis-dependent pathway. A significant amount of nanoparticles transcytose and accumulate at the basolateral membrane. Some anionic but not cationic nanoparticles transited through the degradative lysosomal pathway. Taken together, these observations indicate that cationic nanoparticles, in addition to their potential for drug delivery to epithelia, may be promising carriers for transcytosing drugs to the blood stream.