Polyphosphate Copper Nanospheres Drive Mitochondrial Metabolic Reprogramming via Calcium Phase Separation for...

Precise spatiotemporal control of intracellular Ca²⁺ signaling remains a major bottleneck in reversing tumor glycolytic dominance and reactivating mitochondrial therapies. To overcome this limitation, we developed a polyphosphate (polyP)-engineered nanoplatform that exploits liquid-liquid phase separation (LLPS) to drive calcium-mediated metabolic reprogramming. We discovered that FITC-polyP coacervates with Ca²⁺ to form biomolecular condensates that function as localized Ca²⁺ signaling microdomains. By selectively activating key mitochondrial enzymes, these microdomains shift tumor cells toward a mitochondria-dependent metabolic phenotype. Crucially, disturbing condensate formation via Ca²⁺ chelation or enzymatic degradation prevents this transition, confirming polyP/Ca²⁺ condensates as the indispensable master regulator of mitochondrial metabolic activation. Sustained mitochondrial reactivation creates a primed cellular state that sensitizes tumor cells to cuproptosis. This work establishes a resourceful self-sensitizing nanoplatform that utilizes polyP-induced phase separation to precisely reprogram tumor metabolism and activate cuproptosis, highlighting polyP-induced LLPS as a novel strategy for targeted cancer therapy.