Cancer cell membrane camouflaged biomimetic nanosheets for enhanced chemo-photothermal-starvation therapy and tumor microenvironment remodeling

Tumor microenvironment (TME) featured by dense extracellular matrix (ECM), high interstitial pressure, hypoxia, and immunosuppression hinders the infiltration of nanoparticles (NPs) into tumors, impairing the efficacy of chemotherapy or phototherapy. To overcome these obstacles, we propose a novel biomimetic nano-carrier, B16F10 cell membrane camouflaged heparin-3-bromopyruvate conjugate modified graphene oxide (GO-Hep3BP@membrane, GBM), for the targeted delivery of etoposide (EPT). EPT/GBM accumulates in tumor tissue and is internalized into B16F10 cells relying on homologous targeting ability. GO-mediated hyperthermia could accelerate the release of EPT, destruct ECM, dilate blood vessels, increase oxygen supply, and induce immunogenic cell death (ICD). The acylhydrazone bond-conjugated 3BP is released in acidic environment, suppressing glycolysis for starvation therapy, and reducing lactate efflux to alleviate immunosuppression. The released EPT entered the cell nuclei to exert a chemotherapeutic effect and downregulated the expression of programmed death ligand 1 (PD-L1) by inhibiting epithelial-mesenchymal transition (EMT)/beta-catenin/STT3/PD-L1 signaling. EPT/GBM plus near infrared (NIR) laser treatment activated T lymphocytes and downregulated M2 tumorassociated macrophage (TAM), showing significant efficacy against primary tumors, abscopal tumors and lung metastases. In summary, this study presented a novel combinational strategy that integrated PTT, chemotherapy, starvation therapy and immunotherapy in one system, providing a new perspective for targeted-therapy of melanoma.