Nanotechnology is expanding rapidly and has a range of applications in medicine, electronics, energy production, and consumer products. In nanomedicine, materials in the nanoscale range show great potential in the development of biosensors, nanoscale therapeutics, drug delivery systems, and imaging technologies. A nanomaterial is a material containing structures with one or more external dimensions below 100-200 nm. Many normally ‘inert’ materials become substantially more reactive when downsized to the nanoscale range. This can be beneficial in nanomedicine, but unfortunately may also give rise to nanotoxicity. It is therefore imperative to gather in-depth knowledge of the consequences of interactions between nanomaterials and biological systems. This is important both for optimal exploitation of nanomaterials in biomedicine, and for development of safe and sustainable nanotechnology.
The vast majority of nanomaterials are unable to cross the cellular plasma membrane directly, but depending on their physicochemical properties, they can interact directly with the outer cell surface or be internalization by endocytosis. For example long, fibrous nanomaterials are less likely to be internalized by cells, but have the potential to affect cells by binding to the cell surface. More globular materials, referred to as nanoparticles, are internalized by endocytosis and can potentially interact with the luminal side of the endolysosomal system during vesicular transport and degradation (see Figure 1). The lysosome constitutes an important signaling hub, integrating information on environmental cues, cellular energy levels, and activation of stress response pathways to maintain cellular homeostasis and growth under varying conditions. Thus, accumulation of nanomaterials in the endolysosomal system might have widespread consequences.
Figure 1. Schematic overview of nanomaterial - cell interactions and autophagic pathways. Nanomaterials can either interact with the outer cell surface or be internalized into the endolysosomal pathway. Autophagy can be subdivided into macroautophagy, chaperone-mediated autophagy and microautophagy. During macroautophagy, hereafter referred to as autophagy, the cytoplasmic cargo is sequestered into double-membrane vesicles termed autophagosomes, which fuse with either late endosomes or lysosomes, leading to degradation of the contents by acidic hydrolases. Autophagy provides energy during starvation by degrading unneeded cytoplasmic materials in a largely non-selective process termed bulk autophagy. Another key function is to specifically clear the cells of damaged organelles, toxic protein aggregates, pathogens, or inflammasome components by selective autophagy.
In this project we study the interactions between various nanomaterials and human cells with a particular focus on how nanomaterials affect the cell’s “renovation system” – autophagy. Autophagy is an important cellular degradation- and recycling mechanism that is dependent on functional lysosomes (Figure 1). Previous studies have indicated that various nanomaterials affect autophagy. Nanomaterial exposure leads to accumulation of autophagic structures and markers, and this is commonly taken as evidence for increased autophagy. However, many toxic aspects of nanomaterials may rather be explained by a net inhibition of autophagic degradation capacity, resulting in oxidative stress, inflammation, and accumulation of toxic autophagic cargo. These effects are known risk-factors for diseases such as cancer, chronic inflammatory diseases, and neurodegeneration, which implies that nanomaterial-induced impairment of autophagy can potentially have widespread consequences for human health. Interestingly, anti-cancer treatment may be hampered by the activation of autophagy as a pro-survival mechanism that prevents apoptosis and delays necrosis in cancer cells. This implies that detailed knowledge on how nanomaterials affect autophagy is important both for predicting toxic effects of nanomaterials in different cell types and organs, and also to harness the potential of nanomaterials in biomedicine, for instance in drug delivery.
To study how diverse types of nanomaterials affect autophagic activity, we are establishing a comprehensive screening platform for various types of autophagy. By screening a panel of nanomaterials of different chemical composition and degradability, and with different physical properties such as size, shape and charge, we will characterize the intricate relationship between nanomaterial properties and changes in autophagic activity. Moreover, we aim to elucidate the underlying molecular mechanisms for nanomaterial-mediated effects on autophagy.
Our research is supported by: