The group of Prof. Na Zhang and Prof. Yongjun Liu from the School of Pharmaceutical Sciences of Shandong University has made new progress in nano-edited macrophage cytopharmaceuticals to improve the therapeutic effect of solid tumours, and published in Nature Communications (SCI Q1, Impact Factor: 14.7) entitled “Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours”. PhD candidate Liu Jinhu of Class 2023 is the first author. Prof. Zhang Na and Prof. Liu Yongjun are the paper's corresponding authors. The School of Pharmaceutical Sciences of Shandong University is the first author unit and the only corresponding author unit. Prof. Zhao Huajun, senior lab master Zhang Xinke and other partners in the research group provided important help for this study.

Cytotherapy has made breakthroughs in current cancer therapy, and it will continue to be developed. As a popular marketed therapy, chimeric antigen receptor (CAR) T-cell therapy has benefited many patients with hematologic malignancies. However, its clinical efficacy in solid tumours has been unfavourable. Given the tumour tendency, phagocytosis and killing, antigen presentation and the ability of secreting cytokines to regulate the immune microenvironment for macrophages, macrophage cytopharmaceuticals have attracted much attention. However, the intrinsic immunosuppressive tumour microenvironment highly restricted the effect by re-polarizing macrophages to the anti-inflammatory and protumoural (M2) phenotype instead of the proinflammatory and antitumoural (M1) phenotype, resulting in poor transplantation feasibility and weakened antitumour potency. Therefore, there is growing demand to develop therapeutic macrophage cytopharmaceuticals with the ideal phenotype and high immunological activity.

Fig 1 Schematic illustration of nano-edited macrophage cytopharmaceuticals promoting specific tumour phagocytosis and generating drug exosomes that play a role in triggering an antitumour immune response to combat solid tumours

Here we design nano-edited macrophage cytopharmaceuticals (RILO@MG), harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the macrophage cytopharmaceuticals, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 inhibitor, wrapped in C16-ceramide fused outer membrane vesicles (RILO). The outer membrane vesicles facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed through exosomes. RILO@MG exerts therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.

In recent years, the group of Prof. Zhang Na and Prof. Liu Yongjun has made a series of research achievements in the direction of tumour immune combination therapy and successively developed drug delivery systems based on polarized macrophages (Nanomicro Lett, 2020, 13, 6), nano-cages of reshaping the tumour immune microenvironment (ACS Nano, 2022, 16, 4263-4277), dual-conversion in-situ self-assembly vaccines (Chem Eng J, 2023, 454, 140190), autologous tumour vaccines (Biomaterials, 2023, 297, 122104) and nano-inducers of reshaping the tumour-lymph node immune microenvironment (Nat Commun, 2023, 14, 2248), etc. The above research work has been strongly supported by the National Natural Science Foundation of China, the Excellent Youth Fund of Shandong Province and the Qilu Young Scholars Program at Shandong University.