CE09 - Nanomatériaux et nanotechnologies pour les produits du futur

Nanoparticle lifecycle in human: the key and hazardous role of lysosomal sequestration – CYCLYS

Submission summary

The human body is increasingly exposed to carbon nanotubes and graphenes, as well as two-dimensional analogues, that are developed for industrial use or medical purposes. However, still little is known on the life cycle, long-term fate and potential toxicity in the body of such 1D and 2D nanoparticles (NP) that may persist for months or years due to their slow or inexistent degradability. Most routes of nanomaterial cell uptake converge to the lysosome as intracellular compartment of NP sequestration and degradation. Accumulation of biopersistent NPs in lysosomes may impact lysosomal functions and inhibit the proteolytic activity of the lysosomes. By this way, NPs could interfere with lysosome-associated disorders and could even be involved in their etiology. However, to date, the implications of long-term NP sequestration on lysosomal functions have not been investigated and, conversely, the way 1D and 2D carbon structures can be stored and degraded by endo-lysosomal pathways still remain unclear. In CycLys project, we propose an integrated, multiscale and multidisciplinary methodology to investigate the long term fate of carbon nanotubes, graphenes and emerging 2D analogues in mice and to identify the parameters (structure, materials and functionalization) and mechanisms that governs their persistence, in situ transformations, degradability and potential toxicity in the body. Focusing on lysosome stress and regulation, we seek for a comprehensive investigation of the cell adaptive response to 1D/2D NPs and conversely of the alteration of NPs due to lysosomal processing. We will address the important issue of the proteolytic capacity of cells after exposition to NPs, which, if affected, could lead to chronic toxicity due to accumulation of non-degraded protein aggregates. The overall objective of the CycLys project is thus to correlate the synthetic identity of well characterized NPs to their transformations in human body, and establish a rational on particle design to control their long term fate and toxicity. CycClys project is based on recent discoveries on lysosome functions to establish the link between the accumulation and transformations of 1D and 2D NPs observed at the nanoscale within lysosomes and the biological outcomes at the cellular and tissue levels by focusing on lysosome stress and regulation. While there is no consensus that specifies a reliable biomarker of nanotoxicity, the most widely accepted paradigms have been oxidative stress and inflammation. In this context, the CycClys project has the ambition to bring novel insights in the emerging relationship between lysosomal sensing, NP storage and degradation and proteolytic activity of human cells. We seek for a comprehensive investigation of the cell adaptive response to 1D/2D nanostructures and conversely of the alteration of NPs due to lysosomal processing by addressing the following three major issues. (i) The potential adaptation of the lysosomal pathways to NP sequestration and biopersistence, (ii) The mechanisms of long term degradation of 1D and 2D NPs in lysosomal compartments depending on NP characteristics, (iii) The potential interactions of 1D and 2D NPs with the genesis and/or severity of lysosome-associated diseases. The novelty and originality of the CycClys project is to gather a multidisciplinary consortium with cutting-edge approaches in nanophysics, nanotechnology, advanced microscopy and cell biology to unravel the emerging issue of lysosomal stress due to CNP accumulation and conversely the biotransformations of CNPs induced by lysosomal processing. Moreover, the fate of well-characterized 1D and 2D NPs will be assessed comparatively for the first time in vitro and in vivo to examine potential interference with lysosome-associated diseases and to identify key parameters for safe-by-design development of these nanomaterials. Such comparative evaluation is essentiel to the safe implementation of nanotechnology-based products.

Project coordination

Florence GAZEAU (Laboratoire Matière et Systèmes Complexes)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

MSC Laboratoire Matière et Systèmes Complexes
ICT Immunopathologie et Chimie Thérapeutique
MPQ Laboratoire Matériaux et Phénomènes Quantiques
Neurophotonique
IGPS Institut Galien Paris Sud

Help of the ANR 453,921 euros
Beginning and duration of the scientific project: October 2018 - 36 Months

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