Fig. 3

Lysosomal acidification-modulating agents. a Schematic representation of lysosomal acidification modulation by small molecules and lysosome-targeting  nanomedicine. b C381 and EN6 activate V-ATPase to promote the proton-pumping capacity of the enzyme complex. c Cyclic adenosine monophosphate (cAMP, regulator of lysosomal pH) and NKH-477 (adenylyl cyclase activator) increase the intracellular content of cAMP, which is essential for maintaining lysosomal acidification. d Targeting ion channels, such as activating TRPML1 by SF-22 and inhibiting TPC2 by tetrandrine, allows for a balance of ions in the lysosome lumen to maintain lysosomal acidification. e Curcumin analog C1 and PF11 activate transcription factor EB (TFEB) and increase its nuclear localization to enable the expression of lysosomal components and enhance luminal acidification. f OSI-027 and PP242 acidify lysosomes by inhibiting mTOR signaling. g Lysosome-targeting  nanoparticles (NPs) or nucleolipid nanoemulsions (NL-NEs) formed by various chemical compositions. Compositions of the NPs or NL-NEs shown are based on the most widely used formulations that have demonstrated significant efficacy, although they are modulable and can be further optimized to serve different purposes. The NPs or NL-NEs have a size of 100–200 nm, polydispersity (PDI) of 0.1–0.2 (which indicates a monodisperse population), and abilities to cross the blood-brain barrier (BBB) at 5%–15% of injected dose and lower lysosomal pH by 0.5–3.0 pH units. *The reported values for BBB penetration are only applicable to PLGA NPs and AcNPs; PaNPs and acidic NL-NEs have not been characterized. PLGA NPs, Poly(lactic-co-glycolic acid) NPs; AcNPs, Acidic NPs; PaNPs, Photo-activated NPs; Acidic NL-NEs, Acidic nucleolipid nanoemulsions; LA, Lactic acid; GA, Glycolic acid; TFSA, Tetrafluorosuccinic acid; SA, Succinic acid. Schematics were created by BioRender and chemical structures were drawn by ChemDraw.