Exposure of mitochondrial parkinsonian neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) to PC-12 cells results in significant cell death, decreases lysosomal acidity, and inhibits autophagic flux. Biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of ≈100 nm diameter localize to the lysosome, degrade, and subsequently release their acidic components to acidify the local lysosomal environment. The performance of PLGA NPs with different lysosomal pH modulating capabilities is investigated in PC-12 cells under MPP+ induced mitochondrial toxicity. PLGA NPs perform in a compositional dependent manner, where NPs with a higher glycolic acid to lactic acid ratio content degrade faster and yield greater degrees of lysosomal pH modulation as well as autophagic flux modulation in PC-12 cells under MPP+ insult. These results show that slight compositional changes of the polymeric NP give rise to differing degrees of lysosomal acidification in PC-12 cells and afford improved cellular degradative activity.