Skip to main content
SpringerLink
Log in

A composite peptide-supramolecular microneedle system for melanoma immunotherapy

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Despite recent advances in melanoma treatment through the use of antibody immunotherapy, the clinical benefit remains restricted by its inefficient infiltration and immunosuppression within the tumor microenvironment (TME). In addition, immune-related adverse events (irAEs) have often occurred due to the off-target binding of therapeutic drugs to normal tissues after systematic administration. Herein, we constructed an integrated and cascaded drug delivery system for the treatment of melanoma. In addition to blocking the programmed cell death protein 1 or its ligand (PD-1/PD-L1) axis, the PD-L1 targeting peptide (FE) with spherical micelle self-assembly characteristics could also effectively encapsulate the immune adjuvant resiquimod (R848), and form a complete nano drug. FER was further integrated into tumor-responsive microneedles (MNs) to establish FER@MN and could reach the cascaded functions. FER could be sustainedly released from the MN system and disassemble into monomers, achieving PD-1/PD-L1 axis blockade whilst reprogramming the immunosuppressive TME. Notably, FER@MN permits the controllable release and retention enhancement of the targeting peptide in the TME, thus causing prolonged PD-L1 blockade effect. It is demonstrated that this synergistic treatment could efficiently inhibit melanoma growth, providing a new strategy for the combination treatment of melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Häuser, W.; Ablin, J.; Fitzcharles, M. A.; Littlejohn, G.; Luciano, J. V.; Usui, C.; Walitt, B. Fibromyalgia. Nat. Rev. Dis. Primers 2015, 1, 15022.

    Google Scholar 

  2. Bu, J.; Nair, A.; Iida, M.; Jeong, W. J.; Poellmann, M. J.; Mudd, K.; Kubiatowicz, L. J.; Liu, E. W.; Wheeler, D. L.; Hong, S. An avidity-based PD-L1 antagonist using nanoparticle-antibody conjugates for enhanced immunotherapy. Nano Lett. 2020, 20, 4901–4909.

    CAS  Google Scholar 

  3. Zhang, X. D.; Wang, J. Q.; Chen, Z. W.; Hu, Q. Y.; Wang, C.; Yan, J. J.; Dotti, G.; Huang, P.; Gu, Z. Engineering PD-1-presenting platelets for cancer immunotherapy. Nano Lett. 2018, 18, 5716–5725.

    CAS  Google Scholar 

  4. Nam, J.; Son, S.; Park, K. S.; Zou, W. P.; Shea, L. D.; Moon, J. J. Cancer nanomedicine for combination cancer immunotherapy. Nat. Rev. Mater. 2019, 4, 398–414.

    Google Scholar 

  5. Topalian, S. L.; Taube, J. M.; Anders, R. A.; Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 2016, 16, 275–287.

    CAS  Google Scholar 

  6. Sharma, P.; Hu-Lieskovan, S.; Wargo, J. A.; Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017, 168, 707–723.

    CAS  Google Scholar 

  7. Hu, M.; Zhang, J.; Yu, Y. L.; Tu, K.; Yang, T.; Wang, Y.; Hu, Q.; Kong, L.; Zhang, Z. P. Injectable liquid crystal formation system for reshaping tumor immunosuppressive microenvironment to boost antitumor immunity: Postoperative chemoimmunotherapy. Small 2020, 16, 2004905.

    CAS  Google Scholar 

  8. Sun, M. Q.; Yao, S. B.; Fan, L. Y.; Fang, Z. G.; Miao, W. B.; Hu, Z. Y.; Wang, Z. H. Fibroblast activation protein-α responsive peptide assembling prodrug nanoparticles for remodeling the immunosuppressive microenvironment and boosting cancer immunotherapy. Small 2022, 18, 2106296.

    CAS  Google Scholar 

  9. Jeong, W. J.; Choi, S. H.; Jin, K. S.; Lim, Y. B. Tuning oligovalent biomacromolecular interfaces using double-layered α-helical coiled-coil nanoassemblies from lariat-type building blocks. ACS Macro Lett. 2016, 5, 1406–1410.

    CAS  Google Scholar 

  10. Lau, J. L.; Dunn, M. K. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 2018, 26, 2700–2707.

    CAS  Google Scholar 

  11. Yin, H. W.; Zhou, X. M.; Huang, Y. H.; King, G. J.; Collins, B. M.; Gao, Y. F.; Craik, D. J.; Wang, C. K. Rational design of potent peptide inhibitors of the PD-1: PD-L1 interaction for cancer immunotherapy. J. Am. Chem. Soc. 2021, 143, 18536–18547.

    CAS  Google Scholar 

  12. Fu, L. P.; Zhang, J. H.; Wu, C. C.; Wang, W. Z.; Wang, D.; Hu, Z. Y.; Wang, Z. H. A novel PD-L1 targeting peptide self-assembled nanofibers for sensitive tumor imaging and photothermal immunotherapy in vivo. Nano Res. 2022, 15, 7286–7294.

    CAS  Google Scholar 

  13. Zhang, C.; Gao, F.; Wu, W.; Qiu, W. X.; Zhang, L.; Li, R. Q.; Zhuang, Z. N.; Yu, W. Y.; Cheng, H.; Zhang, X. Z. Enzyme-driven membrane-targeted chimeric peptide for enhanced tumor photodynamic immunotherapy. ACS Nano 2019, 13, 11249–11262.

    CAS  Google Scholar 

  14. Xiao, W. Y.; Wang, Y.; An, H. W.; Hou, D. Y.; Mamuti, M.; Wang, M. D.; Wang, J.; Xu, W. H.; Hu, L. M.; Wang, H. Click reaction-assisted peptide immune checkpoint blockade for solid tumor treatment. ACS Appl. Mater. Interfaces 2020, 12, 40042–40051.

    CAS  Google Scholar 

  15. Zhang, L. G.; Su, T.; He, B.; Gu, Z. W. Self-assembly polyrotaxanes nanoparticles as carriers for anticancer drug methotrexate delivery. Nano-Micro Lett. 2014, 6, 108–115.

    CAS  Google Scholar 

  16. Xia, X. L.; Yang, X. Y.; Huang, W.; Xia, X. X.; Yan, D. Y. Self-assembled nanomicelles of affibody-drug conjugate with excellent therapeutic property to cure ovary and breast cancers. Nano-Micro Lett. 2022, 14, 33.

    CAS  Google Scholar 

  17. Dong, R. J.; Zhou, Y. F.; Huang, X. H.; Zhu, X. Y.; Lu, Y. F.; Shen, J. Functional supramolecular polymers for biomedical applications. Adv. Mater. 2015, 27, 498–526.

    CAS  Google Scholar 

  18. Cheng, H.; Cheng, Y. J.; Bhasin, S.; Zhu, J. Y.; Xu, X. D.; Zhuo, R. X.; Zhang, X. Z. Complementary hydrogen bonding interaction triggered co-assembly of an amphiphilic peptide and an anti-tumor drug. Chem. Commun. 2015, 51, 6936–6939.

    CAS  Google Scholar 

  19. Zou, R. F.; Wang, Q.; Wu, J. C.; Wu, J. X.; Schmuck, C.; Tian, H. Peptide self-assembly triggered by metal ions. Chem. Soc. Rev. 2015, 44, 5200–5219.

    CAS  Google Scholar 

  20. Xu, L.; Shen, Q.; Huang, L. Z.; Xu, X. D.; He, H. Y. Chargemediated co-assembly of amphiphilic peptide and antibiotics into supramolecular hydrogel with antibacterial activity. Front. Bioeng. Biotechnol. 2020, 8, 629452.

    Google Scholar 

  21. Cao, M. W.; Lu, S.; Wang, N. N.; Xu, H.; Cox, H.; Li, R. H.; Waigh, T.; Han, Y. C.; Wang, Y. L.; Lu, J. R. Enzyme-triggered morphological transition of peptide nanostructures for tumor-targeted drug delivery and enhanced cancer therapy. ACS Appl. Mater. Interfaces 2019, 11, 16357–16366.

    CAS  Google Scholar 

  22. Ren, C. H.; Gao, Y.; Guan, Y.; Wang, Z. Y.; Yang, L. J.; Gao, J.; Fan, H. R.; Liu, J. F. Carrier-free supramolecular hydrogel composed of dual drugs for conquering drug resistance. ACS Appl. Mater. Interfaces 2019, 11, 33706–33715.

    CAS  Google Scholar 

  23. Li, I. C.; Moore, A. N.; Hartgerink, J. D. “Missing tooth” multidomain peptide nanofibers for delivery of small molecule drugs. Biomacromolecules 2016, 17, 2087–2095.

    CAS  Google Scholar 

  24. Shi, L.; Kuang, D. Q.; Ma, X. M.; Jalalah, M.; Alsareii, S. A.; Gao, T.; Harraz, F. A.; Yang, J.; Li, G. X. Peptide assembled in a nano-confined space as a molecular rectifier for the availability of ionic current modulation. Nano Lett. 2022, 22, 1083–1090.

    CAS  Google Scholar 

  25. Su, Z. Q.; Shen, H. Y.; Wang, H. X.; Wang, J. H.; Li, J. F.; Nienhaus, G. U.; Shang, L.; Wei, G. Motif-designed peptide nanofibers decorated with graphene quantum dots for simultaneous targeting and imaging of tumor cells. Adv. Funct. Mater. 2015, 25, 5472–5478.

    CAS  Google Scholar 

  26. Yang, J.; An, H. W.; Wang, H. Self-assembled peptide drug delivery systems. ACS Appl. Bio Mater. 2021, 4, 24–46.

    CAS  Google Scholar 

  27. Song, Y. L.; Wang, Y. D.; Wang, S. Y.; Cheng, Y.; Lu, Q. L.; Yang, L. F.; Tan, F. P.; Li, N. Immune-adjuvant loaded Bi2Se3 nanocage for photothermal-improved PD-L1 checkpoint blockade immune-tumor metastasis therapy. Nano Res. 2019, 12, 1770–1780.

    CAS  Google Scholar 

  28. Song, Y. Q.; Li, M. M.; Song, N.; Liu, X.; Wu, G. Y.; Zhou, H.; Long, J. F.; Shi, L. Q.; Yu, Z. L. Self-amplifying assembly of peptides in macrophages for enhanced inflammatory treatment. J. Am. Chem. Soc. 2022, 144, 6907–6917.

    CAS  Google Scholar 

  29. Pandit, G.; Roy, K.; Agarwal, U.; Chatterjee, S. Self-assembly mechanism of a peptide-based drug delivery vehicle. ACS Omega 2018, 3, 3143–3155.

    CAS  Google Scholar 

  30. Zhang, F. J.; Hu, C.; Kong, Q. S.; Luo, R. F.; Wang, Y. B. Peptide-/drug-directed self-assembly of hybrid polyurethane hydrogels for wound healing. ACS Appl. Mater. Interfaces 2019, 11, 37147–37155.

    CAS  Google Scholar 

  31. Chen, B.; He, X. Y.; Yi, X. Q.; Zhuo, R. X.; Cheng, S. X. Dual-peptide-functionalized albumin-based nanoparticles with pH-dependent self-assembly behavior for drug delivery. ACS Appl. Mater. Interfaces 2015, 7, 15148–15153.

    CAS  Google Scholar 

  32. Shen, F. Y.; Sun, L. L.; Wang, L. H.; Peng, R.; Fan, C. H.; Liu, Z. Framework nucleic acid immune adjuvant for transdermal delivery based chemo-immunotherapy for malignant melanoma treatment. Nano Lett. 2022, 22, 4509–4518.

    CAS  Google Scholar 

  33. Liu, Q.; Chen, F. Q.; Hou, L.; Shen, L. M.; Zhang, X. Q.; Wang, D. G.; Huang, L. Nanocarrier-mediated chemo-immunotherapy arrested cancer progression and induced tumor dormancy in desmoplastic melanoma. ACS Nano 2018, 12, 7812–7825.

    CAS  Google Scholar 

  34. Hong, X. Y.; Wu, Z. Z.; Chen, L. Z.; Wu, F.; Wei, L. M.; Yuan, W. E. Hydrogel microneedle arrays for transdermal drug delivery. Nano-Micro Lett. 2014, 6, 191–199.

    CAS  Google Scholar 

  35. Ramot, Y.; Haim-Zada, M.; Domb, A. J.; Nyska, A. Biocompatibility and safety of PLA and its copolymers. Adv. Drug Delivery Rev. 2016, 107, 153–162.

    CAS  Google Scholar 

  36. Demir, Y. K.; Akan, Z.; Kerimoglu, O. Characterization of polymeric microneedle arrays for transdermal drug delivery. PLoS One 2013, 8, e77289.

    CAS  Google Scholar 

  37. Larrañeta, E.; Lutton, R. E. M.; Woolfson, A. D.; Donnelly, R. F. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Mater. Sci. Eng. R Rep. 2016, 104, 1–32.

    Google Scholar 

  38. Qu, M. Y.; Kim, H. J.; Zhou, X. W.; Wang, C. R.; Jiang, X.; Zhu, J. X.; Xue, Y. M.; Tebon, P.; Sarabi, S. A.; Ahadian, S. et al. Biodegradable microneedle patch for transdermal gene delivery. Nanoscale 2020, 12, 16724–16729.

    CAS  Google Scholar 

  39. Wang, C.; Ye, Y. Q.; Hochu, G. M.; Sadeghifar, H.; Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PDl antibody. Nano Lett. 2016, 16, 2334–2340.

    CAS  Google Scholar 

  40. Shimizu, T.; Masuda, M.; Minamikawa, H. Supramolecular nanotube architectures based on amphiphilic molecules. Chem. Rev. 2005, 105, 1401–1444.

    CAS  Google Scholar 

  41. Tian, Y. W.; Zhang, L. M.; Liu, F. J.; Wang, M. X.; Li, L. Y.; Guo, M. M.; Xu, H. Y.; Yu, Z. Y.; Wang, W. Z. Multi-stage responsive peptide nanosensor: Anchoring EMT and mitochondria with enhanced fluorescence and boosting tumor apoptosis. Biosens. Bioelectron. 2021, 184, 113235.

    CAS  Google Scholar 

  42. Wang, Y. H.; Jia, F.; Wang, Z. H.; Qian, Y. X.; Fan, L. Y.; Gong, H.; Luo, A. Q.; Sun, J.; Hu, Z. Y.; Wang, W. Z. Boosting the theranostic effect of liposomal probes toward prominin-1 through optimized dual-site targeting. Anal. Chem. 2019, 91, 7245–7253.

    CAS  Google Scholar 

  43. Lin, X.; Lu, X.; Luo, G. S.; Xiang, H. Progress in PD-1/PD-L1 pathway inhibitors: From biomacromolecules to small molecules. Eur. J. Med. Chem. 2020, 186, 111876.

    CAS  Google Scholar 

  44. Magnez, R.; Thiroux, B.; Taront, S.; Segaoula, Z.; Quesnel, B.; Thuru, X. PD-1/PD-L1 binding studies using microscale thermophoresis. Sci. Rep. 2017, 7, 17623.

    Google Scholar 

  45. Luo, Z. M.; Sun, W. J.; Fang, J.; Lee, K.; Li, S.; Gu, Z.; Dokmeci, M. R.; Khademhosseini, A. Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery. Adv. Healthc. Mater. 2019, 8, 1801054.

    Google Scholar 

  46. Zhu, J. X.; Zhou, X. W.; Kim, H. J.; Qu, M. Y.; Jiang, X.; Lee, K.; Ren, L.; Wu, Q. Z.; Wang, C. R.; Zhu, X. M. et al. Gelatin methacryloyl microneedle patches for minimally invasive extraction of skin interstitial fluid. Small 2020, 16, 1905910.

    CAS  Google Scholar 

  47. Rodell, C. B.; Arlauckas, S. P.; Cuccarese, M. F.; Garris, C. S.; Li, R.; Ahmed, M. S.; Kohler, R. H.; Pittet, M. J.; Weissleder, R. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2018, 2, 578–588.

    CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 22074006), Beijing Natural Science Foundation (No. 2222029), and Beijing Institute of Technology Research Fund Program for Young Scholars. We thank the Analysis and Testing Center in Beijing Institute of Technology on the experimental data acquisition.

Author information

Authors and Affiliations

  1. Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, China

    Mengzhen Li, Minxuan Wang, Lingyun Li, Limin Zhang, Bing Ma & Weizhi Wang

Authors
  1. Mengzhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minxuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingyun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Limin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bing Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weizhi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bing Ma or Weizhi Wang.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Wang, M., Li, L. et al. A composite peptide-supramolecular microneedle system for melanoma immunotherapy. Nano Res. 16, 5335–5345 (2023). https://doi.org/10.1007/s12274-022-5236-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-022-5236-z

Keywords

Search

Navigation