Polydopamine‐Integrated Nanomedicine through Dual Metabolic Intervention with Enhanced Photothermal Therapy against Triple‐Negative Breast Cancer

Abstract Combining metabolic therapy with photothermal therapy (PTT) shows promise for the treatment of triple‐negative breast cancer (TNBC). However, a strategy is still required to effectively overcome the metabolic adaptation of TNBC with thermotolerance during thermotherapy, thereby enhancing therapeutic outcomes. In this study, the polydopamine‐integrated nanomedicine is designed, with glucose oxidase (GOx) chemically conjugated to its surface and curcumin (Cur)‐loaded calcium phosphate (CaP) shell. The outer CaP layer disintegrates in response to the acidic environment of tumor cells, releasing calcium ions with the calcium efflux inhibitor Cur, which causes mitochondrial functional disruption by inducing mitochondrial calcium overload. Concurrently, GOx consumes intracellular glucose to inhibit glycolysis. The dual intervention of mitochondrial metabolism and glycolysis serves to counteract the metabolic adaptations in TNBC, effectively blocking the pathways of energy supply, which results in a 56.61% reduction of ATP. In addition, inhibition of ATP production by dual metabolic regulation can downregulate the expression of heat shock proteins (HSPs) and sensitized PTT, the HSP70 level and HSP90 level are downregulated by 25.68% and 41.89%, respectively. This study provides new insights into combining metabolic therapy and PTT for the treatment of TNBC.