Dual-enzyme catalytic nanosystem-mediated ATP depletion strategy for tumor elimination via excessive autophagy pathway

Excessive autophagy is a promising pathway to eliminate tumor cells, which causes excessive damages to overload the degradation capacity of lysosomes. Designing a nanosystem that can compromise the function of lysosomes and induce severe damages simultaneously is essential to activate excessive autophagy, but is still rarely explored. Herein, a dual-enzyme catalytic nanosystem with adenosine triphosphate (ATP) depletion capacity was developed for tumor elimination via the excessive autophagy pathway. This nanosystem consisted of polyvinyl pyrrolidone-stabilized polyaniline (PANI-PVP) core, Pt nanoparticles (NPs) decoration, and glucose oxidase (GOx) payload. After being internalized by tumor cells, this formed PANI-Pt-GOx-PVP NPs could escape from the lysosome through the proton sponge effect, causing lysosomal swelling and rupturing. The Pt-GOx dualenzyme catalytic nanosystem consumes glucose to cause severe ATP shortage. This energy depletion microenvironment can not only generate intracellular damage during the GOx-mediated starvation process, but also induce mitophagy through AMPK activation. The increased accumulation of damage causes excessive autophagy, overloading the degradation capacity of lysosomes. In vivo data demonstrated that tumor growth tendency was significantly suppressed through this ATP depletion-induced excessive autophagy strategy.