(7g) Nanoparticles As Autophagy Activators

Autophagy is the main catabolic pathway in mammalian cells that mediates degradation of cytoplasmic material through the lysosomes. Deficiencies in this fundamental homeostatic process result in accumulation of cellular waste material, which is associated with development of a range of human diseases. A number of nanomaterials induce autophagy—most likely as a response to the presence of what the cell perceives as foreign of aberrant material. While activation of autophagy may lead to enhanced clearance of waste material, it can also induce activation of cell death programs. Moreover, we found that nanoparticles of specific charge and composition can activate the autophagic response but also impair cellular components that mediate degradation, ultimately blocking autophagic flux. Thus, effective strategies aimed at enhancing cellular clearance should not only activate autophagosome formation to compartmentalize toxic material, but also promote autophagosome clearance by the lysosomes. Evidence of co-regulated roles of lysosomes and autophagosomes emerged from the recent discovery of an overarching regulatory gene network (CLEAR, Coordinated Lysosomal Expression and Regulation) and its master regulator, the transcription factor EB (TFEB). Here, we propose a strategy aimed at activating autophagy and promoting cellular clearance using nanoparticles that could potentially impact a number of human diseases associated with autophagic deficiencies. We investigated the effect of physicochemical properties of a number of nanoparticles, namely geometric parameters, charge, and composition, on downstream effects associated with activation of autophagy, namely clearance of toxic autophagic substrates. In summary, this study provides a mechanistic understanding of the interaction of nanomaterials with the lysosome-autophagy system and identifies the design rules to engineer nanoparticles that enhance clearance of toxic cellular waste for therapeutic applications.