Collaborative CuMn diatomic nanozyme to boost nanocatalytic/mild photothermal/chemo-therapy through overcoming therapeutic resistance

The combined mild-temperature photothermal/chemo-therapy has emerged as a promising approach to complement traditional tumor treatment and enhance therapeutic effects while reduce side effects. However, therapeutic resistance caused by up-regulation of heat shock proteins (HSPs) and P-glycoprotein (P-gp) drastically compromises the synergetic therapeutic effect. Herein, we develop a multifunctional CuMn dual-atom nanozyme loaded with the chemotherapeutic agent doxorubicin (DOX@CuMn-DAzymes) for P-gp and HSPs simultaneous silencing induced synergistic trimodal therapy. The resulting CuMn double-atom pairs with significant synergistic effects can efficiently catalyze cascade reactions of catalase (CAT)-like and oxidase (OXD)-like with endogenous H2O2 as the initial reactant to produce highly reactive singlet oxygen (1O2) under the trigger of acidic tumor microenvironment, destroying the P-gp and HSPs in tumor cells. Benefitting from their black polyporous nanocarbon support, DOX@CuMn-DAzymes not only show superior 1064 nm laser triggered photothermal performance, but also possess high DOX encapsulation efficiency and dual pH- and NIR-responsive DOX release properties. Moreover, in vitro and in vivo study results demonstrate that DOX@CuMn-DAzymes effectively overcome therapeutic resistance by boosting intracellular 1O2 level to simultaneously silence P-gp and HSPs, thereby achieving an impressive synergetic therapeutic efficacy.