Cascade Enzyme Catalysis Supported Starvation and Photodynamic Synergistic Therapy for Breast Cancer

Herein, we present the rational design and development of an innovative nanoplatform for synergistic breast cancer therapy through cascade enzymatic reactions, integrating starvation therapy (ST) and photodynamic therapy (PDT). The system is constructed based on biocompatible calcium phosphate (CaP) nanoparticles, which function as nanocarriers for the photosensitizer indocyanine green (ICG), a critical agent for PDT. To overcome the clinical limitations of hypoxia-induced ICG inactivation, we engineered a sequential enzymatic system by co-immobilizing glucose oxidase (GOX) and catalase (CAT) on the CaP surface, followed by encapsulation within a sodium alginate matrix to prevent premature drug degradation. Systematic characterization demonstrates that the as-prepared nanosystem (denoted as ICG/CaP@GOX-CAT@SA) not only maintains excellent biocompatibility but also achieves tumor-specific accumulation through the enhanced permeability and retention effect, subsequently undergoing lysosomal degradation in tumor cells. Mechanistic investigations reveal that the released GOX initiates ST by catalyzing glucose depletion in the tumor microenvironment, while the simultaneously produced hydrogen peroxide is effectively converted to oxygen (O₂) by CAT, thereby ameliorating tumor hypoxia and maintaining sufficient O₂ levels for ICG-mediated PDT. This cascade enzymatic nanoplatform, which orchestrates the sequential reactions of GOX and CAT to synergistically enhance ST and PDT, demonstrates significantly improved anti-tumor efficacy both in vitro and in vivo, offering a promising paradigm for combinatorial cancer therapy.