Self-sufficient copper peroxide loaded pKa-tunable nanoparticles for lysosome-mediated chemodynamic therapy

Chemodynamic therapy (CDT) has recently gained much attention for Fenton chemistry-mediated cancer treatment, but the anti-tumor efficacy of CDT suffers from insufficient amount of endogenous H₂O₂ and inefficient decomposition of metal oxides to catalytic ions. Although tremendous progress has been made to increase the amount of H₂O₂ in the tumor region, the antitumor activity of CDT remains limited due to the suboptimal ionization to release enough amounts of catalytic ions for converting endogenous H₂O₂ to reactive oxygen species (e.g. highly toxic hydroxyl radical ·OH). Here, a series of nanoparticles with tunable acid dissociation constant (pKa) values from 5.2 to 6.2 were prepared to load H₂O₂ self-supplying copper peroxide, which can be used to trap copper peroxide in acidic lysosome to produce ample catalytic ions that convert self-supplied H₂O₂ into ·OH by a robust Fenton reaction. The highly reactive ·OH effectively permeate the lysosomal membrane through lipid peroxidation and thus kill tumor cells in a lysosome-mediated manner. Most importantly, the Fenton reaction is processed inside the lysosomal compartment, which avoids the cytoplasmic antioxidants such as glutathione (GSH) to scavenge ·OH. Overall, this work provides a new strategy to enhance CDT efficacy.