In this article, an
adenosine-triphosphate-regulated (
ATP-regulated) ion transport nanosystem [SQU@
PCN, porphyrinic porous coordination network (
PCN) incorporated with
squaramide (SQU)] was designed and synthesized for homeostatic perturbation
therapy (HPT) and sensitizing
photodynamic therapy (
PDT) of
tumors. It was found that this nanotransporter SQU@
PCN easily accumulated in
tumor sites while avoiding metabolic clearance and side effects. In response to a high expression of
ATP in the
tumor, SQU@
PCN was decomposed because of the strong coordination of
ATP with
metal ligand of
PCN. Subsequently, incorporated SQU was released and then simultaneously transported
chloride ions across membrane of the cell and lysosome along with the
chloride ion concentration gradient. On one hand, influx of
chloride ions by SQU increased intracellular ion concentration, which disrupted ion homeostasis and further induced
tumor cell apoptosis. On the other hand, SQU-medicated coupling transport of H+/Cl- across the lysosomal membrane alkalized the lysosome, resulting in inhibition of autophagy. This SQU-mediated autophagy inhibition would sensitize
PCN-based
PDT since activated autophagy by traditional
PDT would resist and weaken the therapeutic efficacy. In vivo animal test results revealed that combined HPT and sensitized
PDT could realize
tumor eradication while blocking
metastasis, which provided a paradigm for complementary multimodal
tumor treatment.