Engineered IL-21-Expressing Nanovesicles for Co-Delivery of GOX and Ferrocene to Induce Synergistic Anti-Tumor Effects

Glucose oxidase (GOX)-induced starvation is a safe treatment for tumor. However, the non-specific targeting of GOX and the plasticity of tumor metabolism lead to toxic side effects and low tumor mortality. Thus, it is necessary to develop a synergistic strategy with high tumor targeting specificity to enhance the mortality of GOX. In this study, a genetically engineered CD44 targeting peptide (CP) and IL-21 fusion protein-displaying nanovesicles platform (mCP@IL21-Fc-GOX) are designed to efficiently encapsulate GOX and ferrocene (Fc). After reaching the tumor site, IL-21 can be precisely released and targeted to NK cells through the cleavage of MMP-2, thus achieving precise anti-tumor immunotherapy of IL-21. Second, the exposed CP enable mCP-Fc-GOX to be further targeted to tumor cells, completing the synergistic anti-cancer effects of starvation and chemodynamic therapy (CDT) triggered by GOX and Fc. In situ breast cancer models, the results show that mCP@IL21-Fc-GOX not only enhances NK and T cells aggregation in tumor tissue but also achieves precise nutrition deprivation and abundant reactive oxygen species production, thus significantly inhibits tumor growth based on the synergistic function of the immunotherapy, starvation and CDT. Therefore, this work provides a smart nanovesicle platform for achieving precise and safe synergistic anti-tumor therapy.