Engineering ZCIF@GSK Nanoplatform to Overcome Tumor Metabolism: LDHA Inhibition‐Mediated Cuproptosis for Highly Efficient Oncotherapy

Cuproptosis, heavily dependent on copper and mitochondrial tricarboxylic acid (TCA) cycle, can be exploited as a potential oncotherapy. However, the primary metabolic pathway of tumor cells is dependent on glycolysis owing to the overexpression of lactate dehydrogenase A (LDHA), which suppresses high-efficiency cuproptosis oncotherapy. Therefore, inhibiting LDHA to remodel the metabolic pathway of tumor cells could result in sensitizing cuproptosis and, hence, provide a novel strategy to achieve efficient oncotherapy. Accordingly, we herein report a pH-responsive, copper-engineered nanoplatform (ZCIF@GSK) encapsulating the LDHA inhibitor (GSK). ZCIF@GSK initiates the reprogramming of cellular metabolism, thereby achieving efficient cuproptosis. Under the low pH tumor environment, ZCIF@GSK specifically releases GSK to inhibit LDHA. This, in turn, inhibits glycolysis but promotes mitochondrial TCA cycle, to sensitize cuproptosis. Meanwhile, the release kinetics of copper further causes the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and the downregulation of lipoic acid synthase (LIAS), contributing to efficient cuproptosis. Overall, we propose a novel strategy for sensitizing cuproptosis through an LDHA inhibitor. Additionally, we demonstrate that the inhibition of LDHA upregulates the expression of ferredoxin (FDX1), a key regulator of cuproptosis, further promoting the sensitization of cuproptosis and, hence, a promising cuproptosis-based oncotherapy.