nanoAUTOPHAGY - health implications of nanoparticle-induced changes in autophagy

The main aim of the project nanoAUTOPHAGY’s was to identify how various nanoparticles affect the cells’ “renovation system” called autophagy. This knowledge will enable prediction of nanomaterial toxicity and improve the use of nanomaterials in medicine. Autophagy is a cellular renovation mechanism taking place in the lysosomes, which degrades cytoplasmic cargo such as damaged organelles, protein aggregates, microorganisms, and unneeded proteins. The main function is to protect the cells against these potentially harmful components and to generate energy or recycle nutrients. When nanoparticles are taken up by cells, they most often accumulate in lysosomes and have been shown to affect this important lysosomal renovation process. Accumulation of toxic autophagic cargo is a known risk-factor in diseases such as cancer, chronic inflammatory diseases, and neurodegeneration. This implies that nanomaterial-induced impairment of autophagy could potentially have widespread consequences for human health. Our aim was to characterize how various types of nanomaterials affect the autophagic degradation activity, and we therefore established a panel of methods to measure the activity of various types of autophagy. In collaboration with SINTEF we studied a group of polymer nanoparticles developed as drug delivery vehicles. We revealed that small structural differences in the nanoparticle composition affect autophagy at different stages, and we elucidated some of the underlying mechanisms. Specifically, we found that oxidative stress induced by the nanoparticle treatment has a dual effect on autophagy. Low levels of stress promotes autophagy, whereas high levels block autophagy and eventually lead to cell death. We identified some of the underlying signaling mechanisms also for this effect. Furthermore, we have worked with various types of newer polymer- or lipid-based nanomaterials - which have been developed to deliver drugs, such as chemotherapy, or mRNA (similar to those used in COVID-19 vaccines) - and have investigated how such nanomaterials affect autophagy in human cells. We found that the lipid-based nanoparticles induced damage to the lysosomes, but also a specific cellular response that repairs the damage and thus prevents cell death. We identified key molecular mechanisms for this response, which overlapped with mechanisms controlling autophagy. The novel types of polymer-based nanomaterials, which are carriers of chemotherapeutic drugs, and which we worked on in collaboration with researchers from France, did not appear to affect autophagy in human cells and were well tolerated by the cells. These results are promosing in relation to their potential use in biomedicine. In summary, the project has uncovered a spectrum of different effects on autophagy and toxicity in cells treated with different types of nanomaterials, and has identified molecular mechanisms that help explain the differences.

Prosjektet har avdekket et spekter av forskjellige effekter på autofagi og toksisitet i humane celler behandlet med ulike typer nanomaterialer, og har identifisert molekylære mekanismer som bidrar til å forklare forskjellene. Denne nye innsikten gir et viktig bidrag og kunnskapsgrunnlag for videre utvikling av en trygg og bærekraftig bruk av nanomaterialer i biomedisin. Prosjektresultatene vil være relevante og nyttige for forskere som driver videre grunnleggende nanobiologisk forskning, samt for translasjonsforskere, kliniske forskere og klinikere.

In-depth knowledge of the interaction between nanoparticles and biological systems is imperative for optimal exploitation of nanomaterials in biomedicine, and for development of safe and sustainable nanotechnology. Previous studies have indicated that nanoparticles strongly affect autophagy - a lysosomal renovation mechanism responsible for maintaining cellular homeostasis by degrading damaged organelles and protein aggregates. Nanoparticle exposure leads to accumulation of autophagic structures and markers, which 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 could potentially have widespread consequences for human health. In this project we will employ our strong expertise within the fields of autophagy, intracellular transport, and nanoparticle biology to identify the involvement of autophagy in known nanoparticle effects. We will first establish a comprehensive screening platform for detecting functional autophagy both in cellular systems and in vivo (fruit flies). By screening a panel of nanoparticles we will identify the intricate relationship between nanoparticle properties and changes in endolysosomal homeostasis and autophagy. Moreover, we will reveal the wide range of impacts such changes impose both in vitro and in vivo, by determining the impact on stress responses, neurotoxic aggregate-clearance, cell polarity and development. In sum, we anticipate that our studies will substantially improve our knowledge of the biological effects of nanoparticles on cells and organisms, which is key to harness nanomaterials in biomedicine and to predict nanotoxicity.