Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

A collagenase nanogel backpack improves CAR-T cell therapy outcomes in pancreatic cancer

Nature Nanotechnology volume 20, pages 1131–1141 (2025)Cite this article

Subjects

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of haematological malignancies. Challenges in overcoming physical barriers however greatly limit CAR-T cell efficacy in solid tumours. Here we show that an approach based on collagenase nanogel generally improves the outcome of T cell-based therapies, and specifically of CAR-T cell therapy. The nanogels are created by cross-linking collagenase and subsequently modifying them with a CXCR4 antagonist peptide. These nanogels can bind CAR-T cells via receptor–ligand interaction, resulting in cellular backpack delivery systems. The nanogel backpacks modulate tumoural infiltration and localization of CAR-T cells by surmounting physical barriers and disrupting chemokine-mediated CAR-T cell imprisonment, thereby addressing their navigation deficiency within solid tumours. Our approach offers a promising strategy for pancreatic cancer therapy and holds potential for advancing CAR-T cell therapy towards clinical applications.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CAR-T cell-bound nanogel backpack delivery system potentiates CAR-T cell therapy in pancreatic cancer.
Fig. 2: DV1@O-Colase nanogels with high collagenase loading capacity and enzymatic activity were fabricated and characterized.
Fig. 3: DV1@O-Colase nanogels modulated the motility of murine CD8+ T cells and pancreatic cancer cells in vitro.
Fig. 4: DV1@O-Colase nanogels boosted CD8+ T cells trafficking and regulated growth and metastasis of pancreatic cancer in mice.
Fig. 5: CAR-T cell-bound nanogel backpack delivery system potentiated mobility of CAR-T cells in vitro.
Fig. 6: DV1@O-Colase#CAR-T exhibited potent intratumoural trafficking and robust therapeutic efficacy against pancreatic cancer in vivo.

Similar content being viewed by others

Data availability

The authors declare that all of the data supporting the results are available in this paper and the Supplementary Information. Source data are provided with this paper.

References

  1. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Hou, A. J., Chen, L. C. & Chen, Y. Y. Navigating CAR-T cells through the solid-tumour microenvironment. Nat. Rev. Drug Discov. 20, 531–550 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Newick, K., O’Brien, S., Moon, E. & Albelda, S. M. CAR T cell therapy for solid tumors. Annu. Rev. Med. 68, 139–152 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Haas, A. R. et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol. Ther. 27, 1919–1929 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maus, M. V. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lesch, S. et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat. Biomed. Eng. 5, 1246–1260 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Albelda, S. M. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat. Rev. Clin. Oncol. 21, 47–66 (2024).

    Article  PubMed  Google Scholar 

  14. Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pandol, S., Edderkaoui, M., Gukovsky, I., Lugea, A. & Gukovskaya, A. Desmoplasia of pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 7, S44–S47 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl Acad. Sci. USA 116, 1692–1697 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tian, C. et al. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl Acad. Sci. USA 116, 19609–19618 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Watt, J. & Kocher, H. M. The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration. OncoImmunology https://doi.org/10.4161/onci.26788 (2014).

  19. Cox, T. R. The matrix in cancer. Nat. Rev. Cancer 21, 217–238 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Peranzoni, E., Rivas-Caicedo, A., Bougherara, H., Salmon, H. & Donnadieu, E. Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell. Mol. Life Sci. 70, 4431–4448 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Acerbi, I. et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7, 1120–1134 (2015).

    Article  CAS  Google Scholar 

  22. Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Biasci, D. et al. CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc. Natl Acad. Sci. USA 117, 28960–28970 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bockorny, B. et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat. Med. 26, 878–885 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ene-Obong, A. et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 145, 1121–1132 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Wang, Z. et al. Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2119463119 (2022).

  29. Dolor, A. & Szoka, F. C. Digesting a path forward: the utility of collagenase tumor treatment for improved drug delivery. Mol. Pharm. 15, 2069–2083 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zinger, A. et al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano 13, 11008–11021 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, L. et al. Enhanced intracellular transcytosis of nanoparticles by degrading extracellular matrix for deep tissue radiotherapy of pancreatic adenocarcinoma. Nano Lett. 22, 6877–6887 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Zhou, N. et al. Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with d-peptides derived from chemokines. J. Biol. Chem. 277, 17476–17485 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Ansari, S., Mudassir, M., Vijayalekshmi, B. & Chattopadhyay, P. Targeting CXCR4-expressing cancer cells with avidin-poly (lactic-co-glycolic acid) nanoparticle surface modified with biotinylated DV1 peptide. Int. J. Appl. Basic Med. Res. 13, 106–112 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Houg, D. S. & Bijlsma, M. F. The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma. Mol. Cancer https://doi.org/10.1186/s12943-018-0842-9 (2018).

  35. Saur, D. et al. CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer. Gastroenterology 129, 1237–1250 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Xie, Y. et al. Stromal modulation and treatment of metastatic pancreatic cancer with local intraperitoneal triple miRNA/siRNA nanotherapy. ACS Nano 14, 255–271 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao, H. & Heindel, N. D. Determination of degree of substitution of formyl groups in polyaldehyde dextran by the hydroxylamine hydrochloride method. Pharm. Res. 8, 400–402 (1991).

    Article  CAS  PubMed  Google Scholar 

  38. Qian, D. et al. Galectin-1-driven upregulation of SDF-1 on pancreatic stellate cells promotes pancreatic cancer metastasis. Cancer Lett. 397, 43–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Kato, M., Hattori, Y., Kubo, M. & Maitani, Y. Collagenase-1 injection improved tumor distribution and gene expression of cationic lipoplex. Int. J. Pharm. 423, 428–434 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Diener, B., Carrick, L. Jr. & Berk, R. S. In vivo studies with collagenase from Pseudomonas aeruginosa. Infect. Immun. 7, 212–217 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wehrli, M. et al. Mesothelin CAR T cells secreting anti-FAP/anti-CD3 molecules efficiently target pancreatic adenocarcinoma and its stroma. Clin. Cancer Res. 30, 1859–1877 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee, H. H. et al. Therapeutic efficacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models. Neoplasia 24, 98–108 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Adler-Nissen, J. Determination of the degree of hydrolysis of food protein hydrolysates by trinitrobenzenesulfonic acid. J. Agric. Food Chem. 27, 1256–1262 (1979).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (NSFC, numbers 22272091 (Y.L.), U24A20732 (Y.L.) and 82061148009 (Y.L.)). We acknowledge Y. Cheng and Q. Song from the Qilu Hospital of Shandong University for their technical assistance. The Pharmaceutical Biology Sharing Platform and the Advanced Medical Research Institute of Shandong University are acknowledged.

Author information

Author notes

  1. These authors contributed equally: Zhipeng Zhao, Qian Li.

Authors and Affiliations

  1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Zhipeng Zhao, Qian Li, Chenghao Qu, Zeyu Jiang, Guoqing Jia, Gongde Lan & Yuxia Luan

  2. Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, China

    Chenghao Qu

Authors
  1. Zhipeng Zhao
    View author publications

    Search author on:PubMed Google Scholar

  2. Qian Li
    View author publications

    Search author on:PubMed Google Scholar

  3. Chenghao Qu
    View author publications

    Search author on:PubMed Google Scholar

  4. Zeyu Jiang
    View author publications

    Search author on:PubMed Google Scholar

  5. Guoqing Jia
    View author publications

    Search author on:PubMed Google Scholar

  6. Gongde Lan
    View author publications

    Search author on:PubMed Google Scholar

  7. Yuxia Luan
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Z.Z., Q.L. and Y.L. designed the project. Z.Z., Q.L. and Z.J. performed the in vitro cell experiments. G.J. and G.L. assisted in performing the in vivo imaging experiment. Z.Z., Q.L. and C.Q. achieved the in vivo anti-tumour evaluation. Z.Z. and Y.L. wrote the paper. All authors analysed the data, discussed the results and reviewed the paper.

Corresponding author

Correspondence to Yuxia Luan.

Ethics declarations

Competing interests

Z.Z., Q.L. and Y.L. are the inventors of the patents (CN202410362842.5; US18/619,282) related to this research filed by Shandong University. The other authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Shiba Ansari, Yevgeny Brudno and Navin Varadarajan for their contribution to the peer review of this work.

Additional information

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

Extended data

Extended Data Fig. 1 DV1@O-Colase nanogels potentiated the anti-tumor therapy of αPD-1.

a, Schematic diagram for the experimental protocols of anti-tumor evaluation of DV1@O-Colase nanogels in combination with anti-PD-1 therapy. b, Representative bioluminescence images and c, quantification of bioluminescence intensity of tumor growth in C57BL/6 mice during therapy (n = 5 biologically independent mice). d, The body weight of mice during therapy (n = 5 biologically independent mice). e, Representative FCM scatter blots and quantification of the frequency of CD8+ T cells in tumors (n = 5 biologically independent mice). f, Representative FCM scatter blots and quantification of the expression of granzyme B in tumor infiltrating CD8+ T cells (n = 5 biologically independent mice). g, Representative FCM scatter blots and quantification of the expression of IFN-γ in tumor infiltrating CD4+ T cells (n = 5 biologically independent mice). h, Representative FCM scatter blots and quantification of the frequency of Tregs in tumors (n = 5 biologically independent mice). i, Representative FCM scatter blots and quantification of the frequency of MDSCs in tumors (n = 5 biologically independent mice). Data in e–i were recorded in another parallel experiment of b. The experiments were repeated twice independently, with similar results (b–i). Data in c–i were presented as mean ± SD. P values were determined by two-way ANOVA test (c) or one-way ANOVA test (e–i). **P < 0.01, ****P < 0.0001.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–31 and Tables 1–3.

Reporting Summary

Supplementary Data 1

Source data for Supplementary figures.

Source data

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Extended Data Fig. 1

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Z., Li, Q., Qu, C. et al. A collagenase nanogel backpack improves CAR-T cell therapy outcomes in pancreatic cancer. Nat. Nanotechnol. 20, 1131–1141 (2025). https://doi.org/10.1038/s41565-025-01924-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41565-025-01924-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research