Targeted imaging of lysosomal zinc ions with a tetrahedral DNA framework fluorescent reporter

ABSTRACT Abnormal levels of zinc ions within endo-lysosomes have been implicated in the progression of Alzheimer's disease (AD), yet the detection of low-concentration zinc ions at the organelle level remains challenging. Here we report the design of an endo-lysosome-targeted fluorescent reporter, Znluorly, for imaging endogenous zinc ions. Znluorly is constructed from an amphiphilic DNA framework (DNF) with programmable size and shape, which can encapsulate zinc-responsive fluorophores within its hydrophobic nanocavity. We find that the tetrahedral DNFs of 20 bp in the edge length are effectively located within endo-lysosomes, which can detect zinc ions with a detection limit of ∼31.9 nM (a sensitivity that is ∼2.5 times that of the free fluorophore). Given the organelle-targeting ability and high zinc sensitivity of Znluorly, we employ it to detect endogenous endo-lysosomal zinc ions in neuron cells. We monitor the dynamics of zinc levels in AD model cells and zebrafish, corroborating the positive correlation between zinc levels and AD hallmarks including Aβ aggregates and learning/memory impairments. Our study provides a generalizable strategy for organelle-specific theranostic applications.