ABSTRACT 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.
Cheng et al. (Tue,) studied this question.