The protein quality control system is a complex network that promotes the folding and trafficking of newly synthesized proteins and regulates the degradation of misfolded proteins and protein aggregates. Failure of the quality control system to maintain protein homeostasis (or proteostasis) characterizes the cellular pathogenesis of a number of human diseases. In particular, this study focuses on lysosomal storage disorders, a group of inherited metabolic diseases characterized by deficiencies in specific lysosomal hydrolytic activities that result from mutations in genes encoding for lysosomal proteins and consequent buildup of lysosomal storage material. The ultimate goal of this work is to develop cell engineering strategies to modulate cellular quality control machineries that control protein folding, processing, and degradation to restore cellular homeostasis under conditions of proteotoxic stress. Specifically, this study aims to manipulate the lysosome-autophagy system to enhance folding and processing of lysosomal enzymes as well as to enhance the cellular clearance capacity. To achieve this goal, I investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in regulating lysosomal proteostasis and autophagic clearance. Specifically, chemical and genetic modulation of TFEB was found to enhance folding, trafficking and activity of unstable, degradation-prone lysosomal enzymes in in vitro models of lysosomal storage disorders. Moreover, pharmacologic activation of autophagy achieved by treating cells with 2-hydroxypropyl-β-cyclodextrin was found to enhance autophagic clearance of storage material specifically by activating TFEB. To further investigate the molecular mechanism of autophagy induction and activation of autophagic clearance, I tested the impact of polystyrene nanoparticles of different size and surface charge on the lysosome-autophagy system with the ultimate goal to link the physicochemical properties of nanomaterials with the specific nature of the autophagic response activated upon nanomaterial uptake into cells. Efficient autophagic clearance was found to depend highly on the surface charge. Specifically, cell exposure to polystyrene nanoparticles presenting neutral or negative surface charge results in activation of autophagic clearance, whereas cell exposure to polystyrene nanoparticles presenting cationic surface charge results in impairment of lysosomal function and blockage of autophagic flux. Ceria nanoparticles (or nanoceria) are widely used in a variety of applications including as UV blockers and catalysts in industrial processes. Recent studies also revealed that ceria nanoparticles present antioxidant properties, suggesting a potential role of nanoceria in a variety of biomedical applications. In this study, I investigated the impact of ceria nanoparticles stabilized by organic surface coatings on the lysosome-autophagy system, Ceria nanoparticles were found to activate the lysosome-autophagy system and enhance autophagic clearance. In summary, this work provides proof-of-principle demonstration of chemical and biological strategies to activate the lysosome-autophagy system for restoring lysosomal proteostasis and enhancing autophagic clearance in model systems of diseases characterized by deficiencies in lysosomal enzymes activities and aberrant accumulation of undegraded lysosomal substrates. These findings lay the foundation for the development of nanotherapeutics for the treatment of diseases associated with inefficient autophagic clearance.