Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

Abstract

Iron oxide nanoparticles (IONs) have been widely explored for biomedical applications due to their high biocompatibility, surface-coating versatility, and superparamagnetic properties. Upon exposure to an external magnetic field, IONs can be precisely directed to a region of interest and serve as exceptional delivery vehicles and cellular markers. However, the design of nanocarriers that achieve an efficient endocytic uptake, escape lysosomal degradation, and perform precise intracellular functions is still a challenge for their application in translational medicine. This review highlights several aspects that mediate the activation of the endosomal pathways, as well as the different properties that govern endosomal escape and nuclear transfection of magnetic IONs. In particular, we review a variety of ION surface modification alternatives that have emerged for facilitating their endocytic uptake and their timely escape from endosomes, with special emphasis on how these can be manipulated for the rational design of cell-penetrating vehicles. Moreover, additional modifications for enhancing nuclear transfection are also included in the design of therapeutic vehicles that must overcome this barrier. Understanding these mechanisms opens new perspectives in the strategic development of vehicles for cell tracking, cell imaging and the targeted intracellular delivery of drugs and gene therapy sequences and vectors.

Delivery Systems for Nucleic Acids and Proteins: Barriers, Cell Capture Pathways and Nanocarriers

“…Caveolin-dependent endocytosis has also been reported to result in transcellular transport of caveolae, commonly called transcytosis, and explored in specific cell types, including endothelial, fibroblast, smooth muscle, and adipocyte cells [ 71 , 72 , 73 ]. Since endothelial cells line the blood vessels’ inner surface, these transcytosis-based pathways enable nanocarriers to penetrate them through caveolae formation and, eventually, to come across the endothelium.…”

“…Direct translocation of the plasma membrane is a frequent internalization pathway that facilitates cationic nanoparticles’ entry into cells. This mechanism has been attributed to the electrostatic interactions between positively charged nanoparticles and negatively charged surface moieties of the plasma membrane, which are mainly developed by the presence of membrane components such as proteins, glycolipids, and phospholipids [ 73 ]. Another factor influencing the entry of nanoparticles by this pathway is particle size.…”

“…It has been reported that, particles smaller than 20 nm in diameter, usually follow this pathway [ 89 ]. The strong attraction of cationic nanoparticles with the highly abundant and negatively charged components of the inner membrane layer (e.g., phosphatidylserine) generally causes the formation of transient pores that enable nanoparticle translocation towards the cytoplasm ( Figure 2 F) [ 73 , 89 ]. This behavior accounts for the efficient internalization of small cationic nanoparticles.…”

“…The ability of lipid NPs to internalize and escape endosomes has been facilitated by membrane fusion events [ 96 ] ( Figure 4 ). In general, through hydrophobic interactions, the liposomal envelope fuses with the endosomal membrane [ 73 ]. These interactions are facilitated by the protonation of anionic groups of the liposomal envelope, thereby allowing the release of encapsulated cargoes into the cytosol [ 97 ].…”

“…The potential use of MSN for the delivery of DNA and siRNA has attracted much attention due to the ease of binding through pre-adsorbed cationic polymers (e.g., PEI) and facilitated endosomal escape by the presence of titrating charged groups capable of membrane destabilization ( Figure 4 ) [ 73 ]. However, despite these advantages, PEI-modified mesoporous has proven to induce adverse toxicity effects and lower the amount of siRNA delivered.…”