Progressive-composition-transformation-induced enhanced hyperthermia-based nanozyme towards long-lasting and complete therapy of cancer

• Contrasting with traditional cognition, Cu/CuFe 2 O 4 actually consists of CuFe 2 O 4 4 nanocrystal clusters and Cu nanospheres . • Progressive-composition-transformation-induced increasingly enhanced POD-like activity as a new avenue for lasting CDT. • A programmed synergistic therapy strategy to realize “one injection, long-lasting and complete therapy of cancer”. • Mechanism of how CCFOB nanozyme amplifies oxidative stress was carefully revealed. The biggest bottleneck for nanozymes-initiated chemodynamic therapy (CDT) of cancer is that nanozymes cannot continuously yield hydroxyl radicals towards lasting CDT, given their diffusion and clearance from tumor tissues as well as lower tumor accumulation. Herein, based on a composition-transformable bovine serum albumin (BSA) modified Cu/CuFe 2 O 4 (CCFOB) nanozyme , we present a novel avenue to achieve lasting CDT. This CCFOB nanozyme with peroxidase (POD)-like activity and glutathione depletion ability not only amplifies oxidative stress for effective CDT, but exhibits magnetic targeting and imaging-guided simultaneous photothermal therapy (PTT)/magnetic hyperthermia therapy (MHT)/chemotherapy. Contrasting with traditional cognition, we clarify Cu/CuFe 2 O 4 is actually composed of CuFe 2 O 4 nanocrystal clusters and Cu nanospheres . Attractively, for the first time, it is demonstrated that in microenvironment of residual tumors, CCFOB nanozyme could be progressively transformed into BSA modified Cu 2 O/Cu/CuFe 2 O 4 , which renders CCFOB to be a Cu + reservoir to continuingly produce high-reactivity Cu + . Such continuing production of Cu + grants CCFOB nanozyme increasingly enhanced POD-like activity for lasting CDT despite its diffusion and clearance from tumor tissues. Thus, a programmed synergistic therapy strategy starting with high-intensity PTT/MHT/chemotherapy/CDT to eradicate larger tumors, followed by lasting CDT to eliminate residual tumors and prevent tumor recurrence, has been put forward to eventually realize the concept of “one injection, long-lasting and complete therapy of cancer”. This strategy may provide a new insight for the design of other high-activity nanozymes.