A Biomimetic Microparticle Disrupting the Intracellular/Extracellular pH Homeostasis of Tumor Cells for Cancer Chemo-Immunotherapy

The intracellular/extracellular pH balance is crucial for tumor cells to maintain survival and proliferation. Therefore, a variety of strategies have been developed to disrupt this balance for efficient tumor growth suppression. However, most of them focus on either exacerbating intracellular acidity or alleviating extracellular acidification, with a lack of approaches that interfere with both intracellular and extracellular pH. Herein, we developed a biomimetic tumor cell-derived microparticle for tumor-targeted codelivery of syrosingopine (Syr) and doxorubicin prodrug (Dox-EMCH). Syr can inhibit lactate efflux, disrupting pH homeostasis inside and outside the tumor cells. The increased intracellular acidity activates Dox-EMCH to induce immunogenic cell death, while the alleviated acidity outside tumor cells modulates the immunosuppressive tumor microenvironment (TME) by restoring the activities of cytotoxic T lymphocytes and natural killer cells, promoting M1-like macrophage polarization, and inhibiting regulatory T cells. As a result, the biomimetic microparticles initiate orchestrated chemotherapy and immunotherapy for effective tumor suppression by disrupting the intracellular and extracellular pH balance in tumor tissues.