Ceria Nanoparticles Stabilized by Organic Surface Coatings Activate the Lysosome-Autophagy System and Enhance Autophagic Clearance

Abstract

Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome-autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material. We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings (N-acetylglucosamine, polyethylene glycol and polyvinylpyrrolidone) expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system. This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome-autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material.

Mitophagy induced by nanoparticle–peptide conjugates enabling an alternative intracellular trafficking route

“…An elevated autophagy in cells results from stress conditions, which can be induced by a variety of physical, chemical, and biological factors [26e28]. Recently many types of nanomaterials have been reported to introduce autophagic responses in cells [27,29], including quantum dots [30], carbon nanomaterials [31,32], gold or metal oxide nanoparticles [33,34], and polymer nanoparticles [35]. However, mitophagy induced by nanomaterials has not been addressed, nor the demonstration of how this autophagic degradation affects the intracellular trafficking of nanoparticles.…”

Differential autophagic responses to nano-sized materials

“…Ceria nanoparticles, for instance, which have been amply investigated due to their growing commercial scale production and risk of human exposure [38], enhance autophagic clearance [39 ]. Silver nanoparticles, which are also widely used in consumer products and medical devices due to their excellent anti-microbial properties [40], activate autophagy, but also induce oxidative stress and extensive cytotoxicity [41 ].…”

“…Interestingly, 2-hydroxypropyl-beta-cyclodextrin-mediated activation of TFEB was found not to depend on its ability to alter cellular levels of cholesterol [44]. Internalization of nanoceria stabilized by biocompatible surface coatings (N-acetyl-glucosamine, polyethylene glycol, or polyvinylpyrrolidone) also results in TFEB-mediated activation of autophagic clearance [39 ]. Nanoceria functions as a radical scavenger and protects cells from radiation-induced damage and oxidative stress [45].…”

“…Nanoceria functions as a radical scavenger and protects cells from radiation-induced damage and oxidative stress [45]. The increase in cellular clearance of ceroid lipopigment observed in fibroblasts derived from patients with Late Infantile Neuronal Ceroid Lipofuscinosis [39 ] is thus particularly interesting in light of potential therapeutic applications [46].…”

Photosensitizer-Loaded Branched Polyethylenimine-PEGylated Ceria Nanoparticles for Imaging-Guided Synchronous Photochemotherapy

“…A bovine serum albumin derivative conjugated to the self-quenched dye BODIPY (DQ-BSA) was used as a fluorogenic substrate to evaluate lysosome activity. 53 The green fluorescent product BODIPY is produced when lysosomal hydrolases hydrolyze DQ-BSA. Hence, lysosomal activity was evaluated by measuring the intracellular These results suggest that cell death is mainly mediated through the apoptosis pathway.…”