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In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment

Abstract

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.

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Fig. 1: Schematic and characterization of the in situ formed immunotherapeutic fibrin gel.
Fig. 2: Incorporation of CaCO3@fibrin for relieving immunosuppressive TME.
Fig. 3: CD47 blockade for increasing phagocytosis in vitro and exerting antitumour immune responses in vivo.
Fig. 4: aCD47@CaCO3@fibrin for reducing recurrence of B16F10 tumours after surgery.
Fig. 5: aCD47@CaCO3@fibrin for triggering antitumour immune response.
Fig. 6: Local treatment of aCD47@CaCO3@fibrin for systemic antitumour immune response.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from start-up packages from UNC/NC state and UCLA, the Jonsson Comprehensive Cancer Center at UCLA, the Alfred P. Sloan Foundation (Sloan Research Fellowship), the National Key R&D Program of China (2017YFA0205600), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2017ZT07S054) and the National Natural Science Foundation of China (51728301). The authors thank L. Huang at UNC at Chapel Hill for providing the B16F10-Luc-GFP.

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Q.C., G.D. and Z.G. conceived and designed the experiments. Q.C., C.W., X.Z., G.C., Q.H., Ji.W., D.W., Y.Z., H.L., Y.L., G.Y. and X.Z. performed the experiments and analysed data. Q.C., G.C., C.J., Ju.W., G.D. and Z.G. co-wrote the paper. All authors discussed the results and implications and edited the manuscript at all stages.

Corresponding author

Correspondence to Zhen Gu.

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Z.G. and Q.C. have applied for patents related to this study. Z.G. is a scientific co-founder of ZenCapsule Inc.

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Chen, Q., Wang, C., Zhang, X. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nature Nanotech 14, 89–97 (2019). https://doi.org/10.1038/s41565-018-0319-4

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