Tumor Microenvironment-Responsive Biomimetic Self-Assembled Nanomedicine for Precision Combination Therapy against Triple-Negative Breast Cancer.

Although strategic combination of cuproptosis and chemotherapy is emerging as a promising strategy against triple-negative breast cancer (TNBC), current drug delivery systems remain considerable challenges in achieving co-delivery of different formulas, such as complex nanocarrier design, limited drug loading capacity, and insufficient tumor targeting. Herein, cancer cell membrane-camouflaged, self-assembled nanoparticles (DCM@CCM) were fabricated for precision combination therapy against TNBC. In the strategy, the carrier-free self-assembled nanoparticles were one-pot fabricated by co-assembling copper ions (Cu2+), doxorubicin (DOX), and methotrexate (MTX) via hydrogen bonds, π-π stacking and metal-ligand coordination effect, followed by in situ camouflaging with cancer cell membranes. Benefiting from the homologous targeting effect, the developed DCM@CCM could specifically target tumor cells, promoting their cellular uptake. Following internalization into tumor cells, the DCM@CCM disassembled in response to a weakly acidic tumor microenvironment, releasing Cu2+, DOX, and MTX. Importantly, the Cu2+ was reduced to Cu+ by depleting intracellular glutathione, which not only activated cuproptosis but also catalyzed the endogenous hydrogen peroxide into highly toxic hydroxyl radicals via a Fenton-like reaction, resulting in mitochondrial dysfunction. Simultaneously, both DOX and MTX disrupted DNA synthesis to trigger cell apoptosis. Both in vitro and in vivo experiments indicated that DCM@CCM exhibited potent cytotoxicity against TNBC cells and effectively suppressed tumor growth in heterotopic tumor models with minimal side effects. Overall, our study not only provides a promising strategy for precision combination therapy against TNBC but also expands insight for developing nanoscale self-assembly-enabled nanomedicine.