A Biomimetic Nanomachine Reprograms Transmembrane ATP Flux to Induce Tumor‐Selective Bioenergetic Crisis

Cancer cells maintain malignancy via dysregulated adenosine triphosphate (ATP) synthesis and efflux, yet conventional ATP-depleting therapies remain limited by transient efficacy and compensatory resistance. Here, we present a materials-driven strategy for "transmembrane ATP flux reprogramming" that actively exploits extracellular ATP efflux to induce tumor-selective bioenergetic collapse. An octopus-like biomimetic nanomachine (named HSA-ABC) equipped with ATP-responsive modules that enable synchronized photodynamic membrane disruption and apoptosis-triggered ATP release. Multivalent cholesterol anchors guide precise membrane localization, initiating a self-amplifying therapeutic cycle: localized photodynamic membrane perturbation induces ATP release, which in turn gates the synchronized discharge of Chlorin e6 and doxorubicin, amplifying apoptosis and subsequent ATP leakage. This feedforward loop induces a selective bioenergetic crisis in malignant cells while sparing normal cells. In contrast to conventional metabolic interventions, this approach exploits the intrinsic adaptability of cancer cells to provoke self-driven metabolic collapse. This work establishes a new class of metabolically adaptive nanomaterials capable of reprogramming energy flux dynamics, offering a versatile platform for precision anticancer therapy.