Chemically Designed Nanoscale Materials for Controlling Cellular Processes

Abstract

Conspectus Nanoparticles are widely used in various biomedical applications as drug delivery carriers, imaging probes, single-molecule tracking/detection probes, artificial chaperones for inhibiting protein aggregation, and photodynamic therapy materials. One key parameter of these applications is the ability of the nanoparticles to enter into the cell cytoplasm, target different subcellular compartments, and control intracellular processes. This is particularly the case because nanoparticles are designed to interact with subcellular components for the required biomedical performance. However, cells are protected from their surroundings by the cell membrane, which exerts strict control over entry of foreign materials. Thus, nanoparticles need to be designed appropriately so that they can readily cross the cell membrane, target subcellular compartments, and control intracellular processes. In the past few decades there have been great advancements in understanding the principles of cellular uptake of foreign materials. In particular, it has been shown that internalization of foreign materials (small molecules, macromolecules, nanoparticles) is size-dependent: endocytotic uptake of materials requires sizes greater than 10 nm, and materials with sizes of 10–100 nm usually enter into cells by energy-dependent endocytosis via biomembrane-coated vesicles. Direct access to the cytosol is limited to very specific conditions, and endosomal escape of material appears to be the most practical approach for intracellular processing. In this Account, we describe how cellular uptake and intracellular processing of nanoscale materials can be controlled by appropriate design of size and surface chemistry. We first describe the cell membrane structure and principles of cellular uptake of foreign materials followed by their subcellular trafficking. Next, we discuss the designed surface chemistry of a 5–50 nm particle that offers preferential lipid-raft/caveolae-mediated endocytosis over clathrin-mediated endocytosis with minimum endosomal/lysosomal trafficking or energy-independent direct cell membrane translocation (without endocytosis) followed by cytosolic delivery without endosomal/lysosomal trafficking. In particular, we emphasize that the zwitterionic–lipophilic surface property of a nanoparticle offers preferential interaction with the lipid raft region of the cell membrane followed by lipid raft uptake, whereas a lower number of affinity biomolecules (<25) on the nanoparticle surface offers caveolae/lipid-raft uptake, while an arginine/guanidinium-terminated surface along with a size of <10 nm offers direct cell membrane translocation. Finally, we discuss how nanoprobes can be designed by adapting these surface chemistry and size preference principles so that they can readily enter into the cell, label different subcellular compartments, and control intracellular processes such as trafficking kinetics, exocytosis, autophagy, amyloid aggregation, and clearance of toxic amyloid aggregates. The Account ends with a Conclusions ...

Environmental Nanoparticles Reach Human Fetal Brains

“…Experimentally, the internalization of nanosized materials is a complex process that involves direct membrane penetration with NPs free in the cytosol and endocytotic uptake via biomembrane-coated vesicles, requiring NP sizes in the range of 10–100 nm [ 63 , 64 , 65 ]. The presence of highly reactive Fe-rich and Hg NPs ≤ 10 nm inside brain cells brings up the transportation pathway discussed by Panja and Jana [ 65 ]: arginine-terminated Au ≤10 nm enters via energy-independent direct membrane penetration and, as the size increases, there is a switch to energy-dependent endocytotic uptake. A critical issue at stake involves the fetal brain endothelial and pericyte tight junctions (TJs) and lysosomal NPs’ accumulation at PCW 8–15 weeks, potentially impacting the brain–blood barrier (BBB) formation, its regulation, and permeability [ 66 , 67 , 68 ].…”

Cytotoxicity of ZnO nanoparticles under dark conditions via oxygen vacancy dependent reactive oxygen species generation

“…We selected a coating that provides zwitterionic surface charge, as this offers good cell uptake without appreciable cytotoxicity. 42,43…”

“…We have extensively studied and applied this polyacrylate coating on different nanoparticles. 42,43 We have shown that this coating does not convert nanoparticles to organometallic compounds, and the nanoparticles are stable in the cell culture media without any precipitation (ESI, † Fig. S8).…”

“…We selected a coating that provides zwitterionic surface charge, as this offers good cell uptake without appreciable cytotoxicity. 42,43 HeLa or CHO cells were incubated with colloidal nanoparticles and used in imaging and toxicity studies. First, we checked the labeling of the nanoparticles by cells.…”

The Promise of Nanotechnology in Personalized Medicine

“…During the last years, increased knowledge of endocytic processes allowed the design of “smarter” nanoparticles with improved targeting properties [ 13 , 107 ]. Nanoparticles with a size ranging from 100 to 500 nm are usually internalized through a clathrin-dependent endocytosis pathway [ 108 , 109 ].…”