NIR-II excitation self-assembly nanomedicine for targeted NIR-IIa fluorescence imaging-guided cuproptosis-promoted synergistic therapy against triple-negative breast cancer

Owing to easy copper efflux, the deficiency of targeting delivery and limited tissue penetration depth of light, the combination therapy of cuproptosis and phototheranostics remains enormous challenges towards triple-negative breast cancer (TNBC). To overcome these obstacles, a NIR-II excitation multifunctional nanomedicine is prepared by self-assembly of targeting aptamers (AS1411) utilizes metallic copper ions as coordination nodes, followed by coated with ultrasmall NIR-II polymer dots (Pdots) with excellent optical performances, forming a carrier-free hybrid nanosystem. After positive targeting into TNBC through specific recognition of aptamer towards cell surface nucleolin, Pdots loaded in nanomedicine enable NIR-IIa fluorescence/NIR-II photoacoustic imagingguided NIR-II photothermal therapy (PTT) under NIR-II (1064 nm) light excitation, achieving precise phototheranostics of TNBC tumors. The loaded Cu(II) is reduced to cytotoxic Cu(I) by intracellular glutathione (GSH) and ferredoxin 1 (FDX1), synchronously enabling chemodynamic therapy (CDT) and inducing cuproptosis against TNBC. NIR-II PTT and GSH depletion further enhance therapeutic efficiency of CDT and cuprptosis through cell sensitization. This work provides a new attempt to integrate NIR-II phototheranostics and cuproptosis into a single nanoplatform with targeting capability for synergistic therapy of TNBC.