Water-dispersible fluorescent COFs disturb lysosomal autophagy to boost cascading enzymatic chemodynamic–starvation therapy†

Cascading enzymatic therapy is a promising approach in cancer treatment. However, its effectiveness is often hindered by enzyme inactivation, limited exposure of active sites, cancer cell self-protection mechanisms such as autophagy, and non-specific toxicity, which can lead to treatment failure. To address these challenges, we used a low-temperature aqueous-phase synthesis method to create semi-crystalline, water-dispersible fluorescent COF nanospheres. These nanospheres can stably load glucose oxidase (GOx) and ultrafine Fe₂O₃ nanozymes, allowing for convenient coating with tumor cell membranes to form a uniform tumor-targeted cascading enzymatic nanosystem (CFGM). This system promotes a cycle of tumor glucose depletion, reactive oxygen species (ROS) generation, and oxygen production, facilitating tumor-targeted starvation therapy (ST) and chemodynamic therapy (CDT). Notably, the semi-crystalline COF carrier within this system can degrade slowly under mildly acidic conditions, forming large aggregates that damage lysosomes and disrupt lysosomal autophagy, thereby eliminating the autophagy protection of cancer cells activated by the combined ST. This synergistic approach enhances the catalytic inhibition of tumors. Our research thus provides an alternative COF-based platform and strategy for effective cancer treatment.