Biodegradable copper peroxide decorated hollow polydopamine nanocomposite as effective chloroperoxidase delivery carrier for enhancing enzyme dynamic therapy via self-activated cascade reactions

Recently, enzyme dynamic therapy (EDT) has gained enormous attraction in cancer therapy. However, the efficiency of EDT is still largely restricted by the inefficient delivery efficiency of chloroperoxidase (CPO) and the insufficient hydrogen peroxide (H2O2) content in the tumor microenvironment (TME). In the present work, a biodegradable cupper peroxide decorated hollow polydopamine nanocomposite (HPDCP) with surface functionalization of PEGlated tumor targeting peptide RGD (PEG-RGD) was designed for effective CPO delivery. The resultant nanosystem of HPDCP@CPO@PEG-RGD displayed high CPO delivery efficiency to breast tumors without comprising the enzyme activity. Moreover, the nanosystem can dissociate rapidly in acidic TME by supplying substantial H2O2 and simultaneously releasing Cu2+ and CPO, followed by initiating self-activated cascade reactions. At the one hand, the self-supplied H2O2 greatly enhanced the singlet oxygen (1O2) generation via the CPO-mediated enzyme dynamic reaction. At the other hand, substantial hydroxyl radical (center dot OH) was produced via the Cu2+-driven Fenton reaction for chemodynamic therapy (CDT). Therefore, the anticancer efficiency of EDT was significantly enhanced due to the synergistic EDT/CDT effect. Mechanism study revealed that 1O2/center dot OH generated by HPDCP@CPO@PEG-RGD synergistically inhibited breast cancer cells by firstly causing severe lipid peroxidation, followed by triggering mitochondria-mediated apoptosis and causing irreversible DNA damage by inhibiting the expression of DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP1).