A dissolvable microneedle patch co-delivering Zerumbone and ICG for combined chemo-photothermal therapy of melanoma

1. An, L. et al. A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma. Bioact. Mater. 6(5), 1365–1374. https://doi.org/10.1016/j.bioactmat.2020.10.027 (2021).

   Google Scholar 

2. Lai, M., La Rocca, V., Amato, R., Freer, G. & Pistello, M. Sphingolipid/ceramide pathways and autophagy in the onset and progression of melanoma: Novel therapeutic targets and opportunities. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20143436 (2019).

   Google Scholar 

3. Saginala, K., Barsouk, A., Aluru, J. S., Rawla, P. & Barsouk, A. Epidemiology of melanoma. Med. Sci. (Basel). https://doi.org/10.3390/medsci9040063 (2021).

   Google Scholar 

4. Wei, M. et al. Oxygen-generating transdermal nanoplatform codelivering BRD4 proteolysis-targeting chimera/verteporfin/CaO2 synergistically remodels immunosuppressive melanoma microenvironment to potentiate combination immunotherapy. ACS Nano 19(28), 25830–25850. https://doi.org/10.1021/acsnano.5c04580 (2025).

   Google Scholar 

5. Villani, A. et al. The treatment of advanced melanoma: Therapeutic update. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23126388 (2022).

   Google Scholar 

6. Poklepovic, A. S. & Luke, J. J. Considering adjuvant therapy for stage II melanoma. Cancer 126(6), 1166–1174. https://doi.org/10.1002/cncr.32585 (2020).

   Google Scholar 

7. Tu, L. et al. Ultrasound-controlled drug release and drug activation for cancer therapy. Exploration (Beijing) 1(3), 20210023. https://doi.org/10.1002/exp.20210023 (2021).

   Google Scholar 

8. Wang, Y. et al. Engineering ferrite nanoparticles with enhanced magnetic response for advanced biomedical applications. Mater. Today Adv. 8, 100119. https://doi.org/10.1016/j.mtadv.2020.100119 (2020).

   Google Scholar 

9. Zhao, Y. et al. Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma. Acta Biomater. 135, 164–178. https://doi.org/10.1016/j.actbio.2021.09.009 (2021).

   Google Scholar 

10. Sousa-Junior, A. A. et al. Immunogenic cell death photothermally mediated by erythrocyte membrane-coated magnetofluorescent nanocarriers improves survival in sarcoma model. Pharmaceutics https://doi.org/10.3390/pharmaceutics15030943 (2023).

    Google Scholar 

11. Huang, Y. et al. Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer. Nat. Commun. https://doi.org/10.1038/s41467-021-24564-0 (2021).

    Google Scholar 

12. Yin, Y. et al. Microneedle patch-involved local therapy synergized with immune checkpoint inhibitor for pre- and post-operative cancer treatment. J. Control Release 379, 678–695. https://doi.org/10.1016/j.jconrel.2025.01.051 (2025).

    Google Scholar 

13. Wei, S., Quan, G., Lu, C., Pan, X. & Wu, C. Dissolving microneedles integrated with pH-responsive micelles containing AIEgen with ultra-photostability for enhancing melanoma photothermal therapy. Biomater. Sci. 8(20), 5739–5750. https://doi.org/10.1039/d0bm00914h (2020).

    Google Scholar 

14. Shirata, C. et al. Near-infrared photothermal/photodynamic therapy with indocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress. Sci. Rep. 7(1), 13958. https://doi.org/10.1038/s41598-017-14401-0 (2017).

    Google Scholar 

15. Dong, X. et al. Fluorescence imaging guided CpG nanoparticles-loaded IR820-hydrogel for synergistic photothermal immunotherapy. Biomaterials 209, 111–125. https://doi.org/10.1016/j.biomaterials.2019.04.024 (2019).

    Google Scholar 

16. Hari Prasad, D. et al. Bioactive Compounds from Zingiber montanum and their pharmacological activities with focus on Zerumbone. Appl. Sci. 11(21), 10205. https://doi.org/10.3390/app112110205 (2021).

    Google Scholar 

17. Oh, T. I. et al. Zerumbone, a tropical ginger sesquiterpene of Zingiber officinale roscoe, Attenuates α-MSH-induced melanogenesis in B16F10 cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19103149 (2018).

    Google Scholar 

18. Girisa, S. et al. Potential of Zerumbone as an anti-cancer agent. Molecules https://doi.org/10.3390/molecules24040734 (2019).

    Google Scholar 

19. Kalantari, K. et al. A Review of the biomedical applications of Zerumbone and the techniques for its extraction from ginger rhizomes. Molecules https://doi.org/10.3390/molecules22101645 (2017).

    Google Scholar 

20. Li, X., Zhao, Z., Zhang, M., Ling, G. & Zhang, P. Research progress of microneedles in the treatment of melanoma. J. Control Release 348, 631–647. https://doi.org/10.1016/j.jconrel.2022.06.021 (2022).

    Google Scholar 

21. Han, Y. et al. Microneedle-based approaches for skin disease treatment. Nano-Micro Lett. https://doi.org/10.1007/s40820-025-01662-y (2025).

    Google Scholar 

22. Dabholkar, N. et al. Biodegradable microneedles fabricated with carbohydrates and proteins: Revolutionary approach for transdermal drug delivery. Int. J. Biol. Macromol. 170, 602–621. https://doi.org/10.1016/j.ijbiomac.2020.12.177 (2021).

    Google Scholar 

23. Liu, C., Zhao, Z., Lv, H., Yu, J. & Zhang, P. Microneedles-mediated drug delivery system for the diagnosis and treatment of melanoma. Coll. Surf. B Biointerfaces. 219, 112818. https://doi.org/10.1016/j.colsurfb.2022.112818 (2022).

    Google Scholar 

24. Zhang, Y. et al. Microneedle system for tissue engineering and regenerative medicine. Exploration (Beijing) 3(1), 20210170. https://doi.org/10.1002/EXP.20210170 (2023).

    Google Scholar 

25. Moreira, A. F. et al. Microneedle-based delivery devices for cancer therapy: A review. Pharmacol. Res. 148, 104438. https://doi.org/10.1016/j.phrs.2019.104438 (2019).

    Google Scholar 

26. Kang, Y. et al. Nanocarrier-based transdermal drug delivery systems for dermatological therapy. Pharmaceutics https://doi.org/10.3390/pharmaceutics16111384 (2024).

    Google Scholar 

27. Hou, A. et al. Rational design of rapidly separating dissolving microneedles for precise drug delivery by balancing the mechanical performance and disintegration rate. Adv. Healthc. Mater. 8(21), e1900898. https://doi.org/10.1002/adhm.201900898 (2019).

    Google Scholar 

28. Duan, W. et al. Bimetallic plasmonic nanozyme-based microneedle for synergistic ferroptosis therapy of melanoma. Adv. Sci. https://doi.org/10.1002/advs.202504203 (2025).

    Google Scholar 

29. Duan, W. et al. Engineering dual-driven pro-angiogenic nanozyme based on porous silicon for synergistic acceleration of burn infected wound healing. Mater Today Bio. 31, 101522. https://doi.org/10.1016/j.mtbio.2025.101522 (2025).

    Google Scholar 

30. Qin, W. et al. Dissolving microneedles with spatiotemporally controlled pulsatile release nanosystem for synergistic chemo-photothermal therapy of melanoma. Theranostics 10(18), 8179–8196. https://doi.org/10.7150/thno.44194 (2020).

    Google Scholar 

31. Tang, L. et al. Micro/nano system-mediated local treatment in conjunction with immune checkpoint inhibitor against advanced-stage malignant melanoma. Chem. Eng. J. https://doi.org/10.1016/j.cej.2024.154499 (2024).

    Google Scholar 

32. Rosa, A. et al. Dietary zerumbone from shampoo ginger: new insights into its antioxidant and anticancer activity. Food Funct. 10(3), 1629–1642. https://doi.org/10.1039/c8fo02395f (2019).

    Google Scholar 

33. Sithara, T. et al. Zerumbone, a cyclic sesquiterpene from Zingiber zerumbet induces apoptosis, cell cycle arrest, and antimigratory effects in SW480 colorectal cancer cells. J. Agric. Food Chem. 66(3), 602–612. https://doi.org/10.1021/acs.jafc.7b04472 (2018).

    Google Scholar 

34. Al Saqr, A. et al. Elucidating the anti-melanoma effect and mechanisms of Hispolon. Life Sci. 256, 117702. https://doi.org/10.1016/j.lfs.2020.117702 (2020).

    Google Scholar 

35. Fakhraei Lahiji, S. et al. Tissue interlocking dissolving microneedles for accurate and efficient transdermal delivery of biomolecules. Sci. Rep. 9(1), 7886. https://doi.org/10.1038/s41598-019-44418-6 (2019).

    Google Scholar 

36. Liu, J., Li, L., Zhang, R. & Xu, Z. P. The adjacent effect between Gd(III) and Cu(II) in layered double hydroxide nanoparticles synergistically enhances T(1)-weighted magnetic resonance imaging contrast. Nanoscale Horiz. 8(2), 279–290. https://doi.org/10.1039/d2nh00478j (2023).

    Google Scholar 

37. Xia, Y. et al. Engineering macrophages for cancer immunotherapy and drug delivery. Adv. Mater. https://doi.org/10.1002/adma.202002054 (2020).

    Google Scholar 

38. Vyas, N. S. et al. Observational study examining the diagnostic practice of Ki67 staining for melanocytic lesions. Am. J. Dermatopathol. 41(7), 488–491. https://doi.org/10.1097/dad.0000000000001379 (2019).

    Google Scholar 

39. King, E. et al. Evaluation of SOX-10 immunohistochemical expression in canine melanoma and non-melanocytic tumors by tissue microarray. Vet. Pathol. 61(6), 896–903. https://doi.org/10.1177/03009858241273318 (2024).

    Google Scholar 

Download references

Authors and Affiliations

1. Department of Dermatology, The First Hospital of Hebei Medical University, NO.89, Donggang Road, Yuhua District, Shijiazhuang City, 050031, Hebei Province, China

   Qing Zhu, Bin Wang, Huijuan Wang, Jiaqing Zhao, Dongxue Wang, Yue Yao, Linxi Zeng & Guoqiang Zhang

2. Department of Pharmacy, Hebei Medical University, NO.361, Zhongshan Road, Changan District, Shijiazhuang City, 050031, Hebei Province, China

   Kaiyi Zhang, Jie Lv, Bai Xiang & Feng Zhao

3. Subcenter of National Clinical Research Center for Skin and Immune Diseases, Shijiazhuang, Hebei Province, China

   Qing Zhu, Bin Wang, Huijuan Wang, Jiaqing Zhao, Dongxue Wang, Yue Yao, Linxi Zeng & Guoqiang Zhang

4. Hebei Provincial Innovation Center of Dermatology and Medical Cosmetology Technology, Shijiazhuang, China

   Qing Zhu, Bin Wang, Huijuan Wang, Jiaqing Zhao, Dongxue Wang, Yue Yao, Linxi Zeng & Guoqiang Zhang

Contributions

QZ wrote the main manuscript text, KZ, BW and JL prepared all figures, HW and JZ review the draft, DW, YY and LZ carried out statistical analysis on the data, BX supervise, FZ and GZ revised the original draft. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Feng Zhao or Guoqiang Zhang.

Competing interests

The authors declare no competing interests.

Publisher’s note

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

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions