Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Turajlic, S. & Swanton, C. Metastasis as an evolutionary process. Science 352, 169–175 (2016).

    CAS  Article  Google Scholar 

  2. 2.

    Wang, C. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat. Biomed. Eng. 1, 0011 (2017).

    Article  Google Scholar 

  3. 3.

    Wang, C. et al. In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci. Transl. Med. 10, eaan3682 (2018).

    Article  Google Scholar 

  4. 4.

    Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Baker, D., Masterson, T., Pace, R., Constable, W. & Wanebo, H. The influence of the surgical wound on local tumor recurrence. Surgery 106, 525–532 (1989).

    CAS  Google Scholar 

  6. 6.

    Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation and cancer. Cell. 140, 883–899 (2010).

    CAS  Article  Google Scholar 

  7. 7.

    Vakkila, J. & Lotze, M. T. Inflammation and necrosis promote tumour growth. Nat. Rev. Immunol. 4, 641–648 (2004).

    CAS  Article  Google Scholar 

  8. 8.

    Albain, K. S. et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. The Lancet 374, 379–386 (2009).

    CAS  Article  Google Scholar 

  9. 9.

    Kwon, E. D. et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc. Natl Acad. Sci. USA 96, 15074–15079 (1999).

    CAS  Article  Google Scholar 

  10. 10.

    Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2015).

    CAS  Article  Google Scholar 

  11. 11.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  Article  Google Scholar 

  12. 12.

    Wang, C., Ye, Y., Hu, Q., Bellotti, A. & Gu, Z. Tailoring biomaterials for cancer immunotherapy: emerging trends and future outlook. Adv. Mater. 29, 1606036 (2017).

    Article  Google Scholar 

  13. 13.

    Chen, Q. et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun. 7, 13193 (2016).

    CAS  Article  Google Scholar 

  14. 14.

    Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).

    CAS  Article  Google Scholar 

  15. 15.

    Calandra, T. & Roger, T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat. Rev. Immunol. 3, 791–800 (2003).

    CAS  Article  Google Scholar 

  16. 16.

    Subramanian, S., Parthasarathy, R., Sen, S., Boder, E. T. & Discher, D. E. Species- and cell type-specific interactions between CD47 and human SIRPα. Blood 107, 2548–2556 (2006).

    CAS  Article  Google Scholar 

  17. 17.

    Edris, B. et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc. Natl Acad. Sci. USA 109, 6656–6661 (2012).

    CAS  Article  Google Scholar 

  18. 18.

    Michaels, A. D. et al. CD47 blockade as an adjuvant immunotherapy for resectable pancreatic cancer. Clin. Cancer Res. 24, 1415–1425 (2018).

    CAS  Article  Google Scholar 

  19. 19.

    Ring, N. G. et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc. Natl Acad. Sci. USA 114, 10578–10585 (2017).

    Article  Google Scholar 

  20. 20.

    Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    CAS  Article  Google Scholar 

  21. 21.

    Kershaw, M. H. & Smyth, M. J. Making macrophages eat cancer. Science 341, 41–42 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Sockolosky, J. T. et al. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc. Natl Acad. Sci. USA 113, 2646–2654 (2016).

    Article  Google Scholar 

  23. 23.

    Huang, Y., Ma, Y., Gao, P. & Yao, Z. Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy. J. Thorac. Dis. 9, E168–E174 (2017).

    Article  Google Scholar 

  24. 24.

    Herberman, R. R., Ortaldo, J. R. & Bonnard, G. D. Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature 277, 221–223 (1979).

    CAS  Article  Google Scholar 

  25. 25.

    Lin, E. Y. & Pollard, J. W. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67, 5064–5066 (2007).

    CAS  Article  Google Scholar 

  26. 26.

    Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    CAS  Article  Google Scholar 

  27. 27.

    Neubert, N. J. et al. T cell–induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl. Med. 10, eaan3311 (2018).

    Article  Google Scholar 

  28. 28.

    Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    CAS  Article  Google Scholar 

  29. 29.

    Wang, Y.-C. et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70, 4840–4849 (2010).

    CAS  Article  Google Scholar 

  30. 30.

    Chanmee, T., Ontong, P., Konno, K. & Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 6, 1670–1690 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Baer, C. et al. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat. Cell Biol. 18, 790–802 (2016).

    CAS  Article  Google Scholar 

  32. 32.

    Lewis, C. E., Harney, A. S. & Pollard, J. W. The multifaceted role of perivascular macrophages in tumors. Cancer Cell. 30, 18–25 (2016).

    CAS  Article  Google Scholar 

  33. 33.

    Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

    CAS  Article  Google Scholar 

  34. 34.

    Martin, P. Wound healing—aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    CAS  Article  Google Scholar 

  35. 35.

    Zhao, Y. et al. A preloaded amorphous calcium carbonate/doxorubicin@silica nanoreactor for ph‐responsive delivery of an anticancer drug. Angew. Chem. Int. Ed. 54, 919–922 (2015).

    CAS  Article  Google Scholar 

  36. 36.

    Lu, Y., Aimetti, A. A., Langer, R. & Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2, 16075 (2017).

    CAS  Article  Google Scholar 

  37. 37.

    Mi, P. et al. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat. Nanotech. 11, 724–730 (2016).

    CAS  Article  Google Scholar 

  38. 38.

    Credo, R., Curtis, C. & Lorand, L. Ca2+-related regulatory function of fibrinogen. Proc. Natl Acad. Sci. USA 75, 4234–4237 (1978).

    CAS  Article  Google Scholar 

  39. 39.

    Chen, Q. et al. A self-assembled albumin-based nanoprobe for in vivo ratiometric photoacoustic pH imaging. Adv. Mater. 27, 6820–6827 (2015).

    CAS  Article  Google Scholar 

  40. 40.

    Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    CAS  Article  Google Scholar 

  41. 41.

    Liu, Q. et al. Nanoparticle-mediated trapping of wnt family member 5A in tumor microenvironments enhances immunotherapy for B-Raf proto-oncogene mutant melanoma. ACS Nano 12, 1250–1261 (2018).

    CAS  Article  Google Scholar 

  42. 42.

    Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578 (2018).

    Article  Google Scholar 

  43. 43.

    Meyer, M. A. et al. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance. Nat. Commun. 9, 1250 (2018).

    Article  Google Scholar 

  44. 44.

    Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).

    CAS  Article  Google Scholar 

  45. 45.

    Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  Article  Google Scholar 

  46. 46.

    Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers and combinations. Sci. Transl. Med. 8, 328rv324 (2016).

    Article  Google Scholar 

  47. 47.

    Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  Article  Google Scholar 

  48. 48.

    Nishiyama, N. et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res. 63, 8977–8983 (2003).

    CAS  Google Scholar 

  49. 49.

    Chen, Q. et al. An albumin-based theranostic nano-agent for dual-modal imaging guided photothermal therapy to inhibit lymphatic metastasis of cancer post surgery. Biomaterials 35, 9355–9362 (2014).

    CAS  Article  Google Scholar 

  50. 50.

    Lee, E. J. et al. Nanocage‐therapeutics prevailing phagocytosis and immunogenic cell death awakens immunity against cancer. Adv. Mater. 30, 1705581 (2018).

    Article  Google Scholar 

Download references


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.

Author information




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.

Ethics declarations

Competing interests

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

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading


Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research