While new exciting applications arise from rapid development of new advanced materials, their lifecycle, from production, processing, to degradation or even combustion, may inevitably result in the release of particulate matter into the environment. [1-3] According to the Organisation for Economic Cooperation and Development (OECD) and the World Health Organization (WHO), inhalation of particulate matter, predominantly of anthropogenic origin, is associated with several million human deaths globally every year. [4-6] While larger particles, deposited in airways, can be efficiently cleared from the bronchial region by the mucociliary escalator, [7] nanomaterials, the term used here for both submicron-sized particles (at least two dimensions below 1 µm) and nanoparticles (at least one dimension below 100 nm), can reach the alveolar region. [7,8] Due to the persistency On a daily basis, people are exposed to a multitude of health-hazardous airborne particulate matter with notable deposition in the fragile alveolar region of the lungs. Hence, there is a great need for identification and prediction of material-associated diseases, currently hindered due to the lack of in-depth understanding of causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modeling, it is determined herein that the long-lasting response to a single exposure can originate from the interplay between the newly discovered nanomaterial quarantining and nanomaterial cycling between different lung cell types. This new insight finally allows prediction of the spectrum of lung inflammation associated with materials of interest using only in vitro measurements and in silico modeling, potentially relating outcomes to material properties for a large number of materials, and thus boosting safe-by-design-based material development. Because of its profound implications for animal-free predictive toxicology, this work paves the way to a more efficient and hazard-free introduction of numerous new advanced materials into our lives.

Many chronic diseases manifest in prolonged inflammation and often ignored dysregulated lipid metabolism. When associated with inhalation of nanomaterials, limited information is available on the relevant molecular events and their causal connections. This prevents reliable prediction of outcomes by efficient testing strategies. To unravel how acute nanomaterial exposure leads to chronic conditions, we employed advanced microscopy and omics in vitro and in vivo together with in silico modelling.For selected metal-oxide nanomaterials, we show that lung epithelial cells survive the exposure by excreting internalized nanomaterials and passivating them on the surface, employing elevated lipid synthesis. Macrophages, on the contrary, lose their integrity whilst degrading the passivized bio-nano agglomerates, releasing the nanomaterials, which are taken up again by the epithelial cells. Constant proinflammatory signalling recruits new phagocytes that feed the vicious cycle of events, resulting in a long-lasting response to a single exposure. The proposed mechanism explains the nanomaterialassociated in vivo chronic outcomes and allows its prediction based on in vitro measurements. Similar mechanisms may trigger other chronic diseases affecting millions of lives worldwide.

The prediction of diseases associated with nanomaterials is currently hampered by an incomplete understanding of the underlying mechanisms. Newly discovered nanomaterial quarantining and counteracting nanomaterial cycling fill that gap allowing Tilen Koklič, Tobias Stoeger, Janez Štrancar, and co-workers to incorporate these main modes of cellular response into a mechanistic model and predict in vivo inflammation solely on animal-free in vitro tests, as described in article number 2003913.