Autophagy is a critical cellular maintenance machinery in cells, and prevents the accumulation of toxic protein aggregates, organelles or lipid droplets through degradation via the lysosome. In macro-autophagy, autophagosome first engulfs around aggregates or cellular debris and subsequently fuses with a lysosome that is sufficiently acidic (pH 4.5–5.5), where the contents are then degraded via lysosomal enzymes. Autophagy inhibition as a result of lysosomal acidification dysfunction (pH > 5.5) have been reported to play a major role in various diseases pathogenesis. Hence, there is a pressing need to target lysosomal pH to rescue autophagy. Nanoparticles are attractive materials which has been shown to be efficiently uptaken into cellular organelles and can serve as an agent to specifically localize into lysosomes and modulate its pH. Lipotoxicity, induced by chronic exposure to free fatty acids, and exposure to neurotoxins (e.g. MPP+), elevates lysosomal pH in pancreatic beta cells (Type II Diabetes, T2D) and hepatocytes (Non-alcoholic fatty liver disease, NAFLD), and PC-12 cells (Parkinson’s Disease), respectively. We first tested the lysosome acidification capability of photo-activable nanoparticles (paNPs) and poly (lactic-co-glycolic) acid nanoparticles (PLGA NPs) in a T2D model. Both NPs lowered lysosomal pH in pancreatic beta cells under lipotoxicity and improved insulin secretion function. However, paNPs only release acids upon UV trigger, limiting its applicability in vivo, while PLGA NPs degrade upon lysosome localization. We further showed that PLGA NPs are able to rescue MPP+ induced cell death in a PD model, though it has a slow degradation rate. To attain the most efficacious nanoparticle with a fast degradation and acidification rate, we synthesized acidic nanoparticles (acNPs) based on tetrafluorosuccinic and succinic acids to form optimized nanoparticles. The acNPs showed faster rescue of cellular function compared to PLGA NPs in the PD model. Finally, we tested the acNPs in NAFLD model, and where lysosomal pH reduction by acNPs restored autophagy, reduced lipid accumulation, and improved mitochondria function in high-fat diet mice. In sum, nanoparticles are of potential therapeutic interest for pathologies associated with lysosomal acidity impairment. Future studies include testing the acNPs in NASH disease model and clinical studies. / 2022-05-18T00:00:00Z