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Dual targeting to immune checkpoints has achieved a better therapeutic efficacy than single targeting due to synergistic extrication of tumour immunity. However, most dual targeting strategies are usually antibody dependent which facing drawbacks of antibodies, such as poor solid tumour penetration and unsatisfied affinity. To meet the challenges, we engineered a cell membrane displaying a fusion protein composed of SIRPa and PD-1 variants, the high-affinity consensus (HAC) of wild-type molecules, and with which prepared nanovesicles (NVs). Through disabling both SIRPa/CD47 and PD-1/PD-L1 signalling, HAC NVs significantly preserved the phagocytosis and antitumour effect ofmacrophages and T cells, respectively. In vivo study revealed that HAC NVs had better tumour penetration than monoclonal antibodies and higher binding affinity to CD47 and PD-L1 on tumour cells compared with the NVs expressing wild-type fusion protein. Exhilaratingly, dual-blockade of CD47 and PD-L1 with HAC NVs exhibited excellent therapeutic efficacy and biosafety. This study provided a novel biomaterial against tumoural immune escape and more importantly an attractive biomimetic technology of protein delivery formulti-targeting therapies. [ABSTRACT FROM AUTHOR]

Different experimental models of hepatocellular carcinoma (HCC) have been used to investigate the biological mechanisms of hepatocarcinogenesis and its progression. However, previous studies have highlighted the difficulty of distinguishing between the tumor cells and stroma in experimental models of HCC. Therefore the aim of the present study was to establish a red-green dual-color fluorescence tracing orthotopic transplantation model of HCC, and investigate its practical values. Stable high red fluorescent protein (RFP)-expressing HepG2 human hepatoma cells and Hepa1-6 mice hepatoma cells were injected into the right liver lobe of green fluorescent protein-expressing nude mice. The growth and metastasis of the tumors were visualized using a whole-body in vivo fluorescence imaging system in real time. HCC tissues were extracted from tumor-bearing mice, and cut into 5-µm serial frozen slices. The organizational structure of the transplanted tumors was observed under a microscope. A dual-color fluorescence tracing orthotopic transplantation tumor model of HCC was successfully established with a success rate of 100%. The growth and metastasis of the tumors were visualized at each stage of development in the tumor-bearing mice. Tumor cells with red fluorescence and host cells with green fluorescence were identified to merge in the reconstruction region of tumor tissue. The invasion, migration, and cell fusion between tumor and host cells was observed clearly. The dual-color fluorescence tracing orthotopic transplantation model of HCC was determined to be a stable and reliable method for tracking tumor progression. Mutual interactions between hepatoma cells and host tissues may be observed directly using this model, further elucidating the development of the tumor microenvironment. [ABSTRACT FROM AUTHOR]