A Quad-Functional On-demand released nanomissile achieves cascade amplification therapy of Triple-Negative breast cancer through reversing multiple resistance

Triple-negative breast cancer (TNBC) remains a serious health issue for women worldwide due to the high malignancy and invasiveness. Despite combination therapies of TNBC have achieved great progress, the efficacy is severely restricted by tumor resistance protein-mediated drug resistance. Herein, a quad-functional on-demand released nanomissile was developed for reversing multiple resistance through inhibiting tumor resistance proteins, achieving cascade amplification therapy of TNBC. This nanomissile, encapsulated IR-780, gambogic acid (GA) and nitric oxide (NO)-releasing donor diethylenetriamine diazeniumdiolate via self-assemble, exhibited a quadruple synergetic effect which inhibited the growth of TNBC. Initially, the exquisite design endowed the nanomissile with prolonged circulation time in vivo and enhanced tumor-targeting capability. After the nanomissile was taken up by tumor cells, the loaded IR780 mediated the low-temperature photothermal therapy under irradiation of NIR light. This photothermal effect and the intracellular acidic stimulation promoted the nanomissile to release NO and GA. The released GA not only achieved low-dose chemotherapy, but also effectively inactivated heat shock protein 90, resulting in breakthrough against photothermal resistance. Finally, the released NO induced tumor gas therapy, and also inactivated P glycoprotein, thereby reversing chemotherapy resistance to enhance GA-mediated chemotherapy. Overall, this quad-functional on-demand released nanomissile enabled a cascade amplification therapy of TNBC through inactivating multiple tumor resistance proteins, showing potential clinical applications.