Exocytosis of Nanoparticles: A Comprehensive Review

Abstract

Both biomedical applications and safety assessments of manufactured nanomaterials require a thorough understanding of the interaction between nanomaterials and cells, including how nanomaterials enter cells, transport within cells, and leave cells. However, compared to the extensively studied uptake and trafficking of nanoparticles (NPs) in cells, less attention has been paid to the exocytosis of NPs. Yet exocytosis is an indispensable process of regulating the content of NPs in cells, which in turn influences, even decides, the toxicity of NPs to cells. A comprehensive understanding of the mechanisms and influencing factors of the exocytosis of NPs is not only essential for the safety assessment of NPs but also helpful for guiding the design of safe and highly effective NP-based materials for various purposes. Herein, we review the current status and progress of studies on the exocytosis of NPs. Firstly, we introduce experimental procedures and considerations. Then, exocytosis mechanisms/pathways are summarized with a detailed introduction of the main pathways (lysosomal and endoplasmic reticulum/Golgi pathway) and the role of microtubules; the patterns of exocytosis kinetics are presented and discussed. Subsequently, the influencing factors (initial content and location of intracellular NPs, physiochemical properties of NPs, cell type, and extracellular conditions) are fully discussed. Although there are inconsistent results, some rules are obtained, like smaller and charged NPs are more easily excreted. Finally, the challenges and future directions in the field have been discussed.

Size-Related Pathway Flux Analysis of Ultrasmall Iron Oxide Nanoparticles in Macrophage Cell RAW264.7 for Safety Evaluation

“…The exocytosis kinetics of nanoparticles coincided well with the single exponential model. The content of nanoparticles in the culture medium increased significantly during the first 4 h and then exocytosis of nanoparticles enhanced slowly after 4 h (Figure B), which coincided with the time needed to reach the maximum exocytosis in most reports . The exocytosis rates reduced continuously due to the decreased driving force resulting from the concentration gradient difference between intracellular and extracellular USIONPs for nanoparticle efflux.…”

“…The content of nanoparticles in the culture medium increased significantly during the first 4 h and then exocytosis of nanoparticles enhanced slowly after 4 h ( Figure 2 B), which coincided with the time needed to reach the maximum exocytosis in most reports. 40 The exocytosis rates reduced continuously due to the decreased driving force resulting from the concentration gradient difference between intracellular and extracellular USIONPs for nanoparticle efflux. Then, the dynamic equilibrium between endocytosis and exocytosis gradually approached; thus, the exocytosis number of nanoparticles did not further increase.…”

Effects of Different Surface Functionalizations of Silica Nanoparticles on Mesenchymal Stem Cells

“…Taken together with these data, these functionalized silica nanoparticles could undergo exocytosis via an alternative mode of exocytotic pathways in addition to β-hexosaminidase activity. Alternative exocytosis pathways include lysosomal and endoplasmic reticulum/Golgi pathways, as well as the role of microtubules and physiochemical properties of intracellular nanoparticles. , In fact, a study revealed that nanoparticles could exit the cell predominantly via unconventional exocytosis, accompanied by enhanced secretion of extracellular vesicles …”

“…Alternative exocytosis pathways include lysosomal and endoplasmic reticulum/Golgi pathways, as well as the role of microtubules and physiochemical properties of intracellular nanoparticles. 35,36 In fact, a study revealed that nanoparticles could exit the cell predominantly via unconventional exocytosis, accompanied by enhanced secretion of extracellular vesicles. 37 Because the ingested nanoparticles were distributed mainly in lysosomes, where they are broken down or encapsulated into the form of lysosomal exocytosis and excreted from the cell, fluorescent LysoTracker Green was used to track the trafficking and localization of nanoparticles in lysosomes.…”

Biotin-functionalized nanoparticles: an overview of recent trends in cancer detection

“…113,114 These nanocarriers can be loaded with drugs or genes and then delivered specifically to cancer cells for targeted therapy. 115–117…”