Fig. 2.

Challenges to intracellular delivery

(A) Entrapment of nanoparticles in endocytic pathways is a significant barrier to efficient delivery. Endocytosis delivers the nanoparticles to (i) the early endosome. Nanoparticles that failed to escape from the early or (ii) the late endosome, face degradation in (iii) the endolysosome, which is produced by fusion with (iv) the lysosome. The harsh milieu of the endocytic compartments due to decrease in pH, changes in shape and composition of these compartments is a significant barrier to drug delivery. Scale bars, 100 nm. Adapted with permission from [50], Copyright 2011, European Molecular Biology Organization. (B) Schematic representations of endothelial glycocalyx. Glycocalyx is composed of hyaluronans, heparin sulfate, proteoglycans, and glycoproteins and impedes nanoparticles interactions with plasma membrane. Electron micrograph depicts the glomerular glycocalyx with the fenestrae (arrows). Scale bar, 100 nm. Adapted with permission from [66], Copyright 2015, Springer Nature. (C) Schematic representation of the cytosolic mobility of particulates. Particles larger than the pores of the cytoskeletons (50 – 70 nm) display restricted diffusion due to cytosolic viscosity. These large particulates are constrained in the medium but will eventually drift following the remodeling of internal structures. Particles smaller than the pore size diffuse with viscosities that are dependent on the strength of the non-specific interactions. If the particles are completely inert, they move freely as if in water. When the particles start to interact with intracellular components, their motions are delayed due to non-specific interactions that can result in a slow Brownian or anomalous motion. This molecular crowding prevents nanoparticles in cytosol from reaching subcellular targets. Reproduced with permission from [83], Copyright 2018, Springer Nature.