Ruthenium Nanozyme@Magnesium silicate nanosheets encapsuled in microneedle patches promote repair of radiation-induced skin defects by remodeling pathological environment

Abstract

Radiotherapy induced skin defect (RISD) is a severe radiotherapy complication with persistent oxidative stress and recurrent excessive reactive oxygen species (ROS), impeding normal tissue repair processes. Nevertheless, the lack of a standardized animal model severely hinders the progress of related research work. We develop a novel strategy for repairing the RISD microenvironment, which combines initial ROS clearance, subsequent inhibition of ROS production and the repair of proliferation related cell pathways/functions. As a proof of concept, a composite microneedle (MN) patch comprising γ-polyglutamic acid as the base and ruthenium (Ru) clusters modified magnesium silicate nanosheets (MSR NSs) as the enzyme-like component is prepared. The Ru clusters have excellent ROS scavenging ability and help activate the peroxisome proliferators activated receptor signaling pathway confirmed by the sequencing analysis while the magnesium silicate is degraded under physiological conditions to release magnesium ions and silicate ions, enhancing cell proliferation, migration, and angiogenesis ability. The radiation induced skin defect animal model is established to evaluate the RISD repair efficacy of our MSR@MN patch in comparison with γPGA-MSR ointment and commercial product Orgotein. The results show that our MSR@MN patch effectively improves the pathological microenvironment of abnormal ROS accumulation, reduces inflammatory response and promotes mature angiogenesis and tissue remodeling.

Keywords

microneedle patch / radiotherapy induced skin defects / ruthenium clusters / skin repair

References

[1] C. H. Ruhlmann, F. Jahn, K. Jordan, K. Dennis, E. Maranzano, A. Molassiotis, F. Roila, P. Feyer, Support. Care Cancer 2016, 25, 309.

[2] Q. Dasgupta, A. Jiang, A. M. Wen, R. J. Mannix, Y. Man, S. Hall, E. Javorsky, D. E. Ingber, Nat. Commun. 2023, 14, 6506.

[3] J. Gomez-Millan, Crit. Rev. Oncol. Hematol. 2009, 71, 70.

[4] D.-H. Ha, S. Chae, J. Y. Lee, J. Y. Kim, J. Yoon, T. Sen, S.-W. Lee, H. J. Kim, J. H. Cho, D.-W. Cho, Biomaterials 2021, 266, 120477.

[5] Z. Zhang, Q. Cao, Y. Xia, C. Cui, Y. Qi, Q. Zhang, Y. Wu, J. Liu, W. Liu, Bioact. Mater. 2024, 31, 408.

[6] W. Chen, Y. Wang, J. Zheng, Y. Chen, C. Zhang, W. Yang, L. Wu, Z. Yang, Y. Wang, C. Shi, Burns Trauma 2023, 11, tkad001.

[7] Z. Wang, Z. Chen, Z. Jiang, P. Luo, L. Liu, Y. Huang, H. Wang, Y. Wang, L. Long, X. Tan, D. Liu, T. Jin, Y. Wang, Y. Wang, F. Liao, C. Zhang, L. Chen, Y. Gan, Y. Liu, F. Yang, C. Huang, H. Miao, J. Chen, T. Cheng, X. Fu, C. Shi, Nat. Commun. 2019, 10, 2538.

[8] J. Xie, M. Zhao, C. Wang, S. Zhu, W. Niu, Y. Yong, L. Zhao, Z. Gu, Chem. Eng. J. 2022, 430, 132866.

[9] Z. Fang, Y. Lv, H. Zhang, Y. He, H. Gao, C. Chen, D. Wang, P. Chen, S. Tang, J. Li, Z. Qiu, X. a. Shi, L. Chen, J. Yang, X. Chen, Acta Biomater. 2023, 159, 111.

[10] D. T. Hass, C. J. Barnstable, Prog. Retin. Eye Res. 2021, 83, 100941.

[11] M. Smolarz, Ł. Skoczylas, M. Gawin, M. Krzyżowska, M. Pietrowska, P. Widłak, Int. J. Mol. Sci. 2022, 23, 4169.

[12] F. Geng, J. Chen, B. Song, Z. Tang, X. Li, S. Zhang, T. Yang, Y. Liu, W. Mo, Y. Zhang, C. Sun, L. Tan, W. Tu, D. Yu, J. Cao, S. Zhang, Cell. Mol. Immunol. 2024, 21, 856.

[13] J. Ge, B. Jia, Y. Wang, Y. Ma, X. Sun, J. Dong, S. Jiang, Z. Li, Adv. Funct. Mater. 2024, 34, 2402781.

[14] J. Liu, Y. Dong, J. Tang, J. Wu, Y. Huang, C. Yao, D. Yang, Nano Today 2024, 55, 102185.

[15] Y. Zheng, X. Chen, Q. Zhang, L. Yang, Q. Chen, Z. Chen, Y. Wang, D. Wu, Adv. Healthcare Mater. 2023, 13, e22302640.

[16] Y. Guo, S. Ding, C. Shang, C. Zhang, M. Li, Q. Zhang, L. Gu, B. C. Heng, S. Zhang, F. Mei, Y. Huang, X. Zhang, M. Xu, J. Jiang, S. Guo, X. Deng, L. Chen, Adv. Mater. 2023, 36, 2306292.

[17] J. Liu, Z. Chen, H. Liu, S. Qin, M. Li, L. Shi, C. Zhou, T. Liao, C. Li, Q. Lv, M. Liu, M. Zou, Y. Deng, Z. Wang, L. Wang, Small 2023, 20, 2305076.

[18] Y. Xu, Y. Luo, Z. Weng, H. Xu, W. Zhang, Q. Li, H. Liu, L. Liu, Y. Wang, X. Liu, L. Liao, X. Wang, ACS Nano 2023, 17, 18732.

[19] W. Zhang, M. Zhao, D. Chu, H. Chen, B. Cui, Q. Ning, X. Wang, Z. Li, S. Cao, J. Li, J. Nanobiotechnol. 2024, 22, 229.

[20] M. Lian, Z. Xue, X. Qiao, C. Liu, S. Zhang, X. Li, C. Huang, Q. Song, W. Yang, X. Chen, T. Wang, Chem 2019, 5, 2378.

[21] H.-M. Huang, P. Bellotti, J. Ma, T. Dalton, F. Glorius, Nat. Rev. Chem 2021, 5, 301.

[22] J. Li, L. Zeng, Z. Wang, H. Chen, S. Fang, J. Wang, C. Y. Cai, E. Xing, X. Liao, Z. W. Li, C. R. Ashby, Z. S. Chen, H. Chao, Y. Pan, Adv. Mater. 2021, 34, 2100245.

[23] C.-Y. Shi, X.-Q. Chen, R. Zeng, H. Lu, Z. Fan, A. Zhang, Org. Lett. 2023, 25, 3870.

[24] Y. Song, J. Min, Y. Guo, R. Li, G. Zou, M. Li, Y. Zang, W. Feng, X. Yao, T. Liu, X. Zhang, J. Yu, Q. Liu, P. Zhang, R. Yu, X. Cao, J. Zhu, K. Dong, G. Wang, X. Bao, Angew. Chem. Int. Ed. 2023, 63, e202313361.

[25] B. Wang, Y. Fang, X. Han, R. Jiang, L. Zhao, X. Yang, J. Jin, A. Han, J. Liu, Angew. Chem. Int. Ed. 2023, 62, e202307133.

[26] C. Liu, M. Rokavec, Z. Huang, H. Hermeking, Cell Death Differ. 2023, 30, 1771.

[27] X. Liu, P. Zhao, X. Wang, L. Wang, Y. Zhu, Y. Song, W. Gao, J. Exp. Clin. Cancer Res. 2019, 38, 184.

[28] F. Cao, L. Jin, Y. Gao, Y. Ding, H. Wen, Z. Qian, C. Zhang, L. Hong, H. Yang, J. Zhang, Z. Tong, W. Wang, X. Chen, Z. Mao, Nat. Nanotechnol. 2023, 18, 617.

[29] E. J. Curvino, E. F. Roe, H. Freire Haddad, A. R. Anderson, M. E. Woodruff, N. L. Votaw, T. Segura, L. P. Hale, J. H. Collier, Nat. Biomed. Eng. 2023, 8, 628.

[30] Q. Fan, Z. Yang, Y. Li, Y. Cheng, Y. Li, Adv. Funct. Mater. 2021, 31, 2101646.

[31] D. Ege, K. Zheng, A. R. Boccaccini, ACS Appl. Bio Mater. 2022, 5, 3608.

[32] J. Ma, C. Wu, Exploration 2022, 2, 20210083.

[33] C. Fan, Q. Xu, R. Hao, C. Wang, Y. Que, Y. Chen, C. Yang, J. Chang, Biomaterials 2022, 287.

[34] J. Xue, C. Qin, C. Wu, Regenerative Biomater. 2023, 10, rbad032.

[35] H. He, W. Huang, S. Zhang, J. Li, J. Zhang, B. Li, J. Xu, Y. Luo, H. Shi, Y. Li, J. Xiao, O. C. Ezekiel, X. Li, J. Wu, Small 2024, 20, 2307458.

[36] S. Li, X. Wang, Z. Yan, T. Wang, Z. Chen, H. Song, Y. Zheng, Adv. Sci. 2023, 10, 2300576.

[37] S. Lyu, Z. Dong, X. Xu, H.-P. Bei, H.-Y. Yuen, C.-W. James Cheung, M.-S. Wong, Y. He, X. Zhao, Bioact. Mater. 2023, 27, 303.

[38] B. M. Allen, K. J. Hiam, C. E. Burnett, A. Venida, R. DeBarge, I. Tenvooren, D. M. Marquez, N. W. Cho, Y. Carmi, M. H. Spitzer, Nat. Med. 2020, 26, 1125.

[39] Y. F. Tian, G. Li, D. X. Xu, Z. Y. Lu, M. Y. Yan, J. Wan, J. Y. Li, Q. Xu, S. Xin, R. Wen, Y. G. Guo, Adv. Mater. 2022, 34, 2200672.

[40] F. Xia, X. Hu, B. Zhang, X. Wang, Y. Guan, P. Lin, Z. Ma, J. Sheng, D. Ling, F. Li, Small 2022, 18, 2201558.

[41] M. Yin, J. Wu, M. Deng, P. Wang, G. Ji, M. Wang, C. Zhou, N. T. Blum, W. Zhang, H. Shi, N. Jia, X. Wang, P. Huang, ACS Nano 2021, 15, 17842.

[42] M. Sang, M. Cho, S. Lim, I. S. Min, Y. Han, C. Lee, J. Shin, K. Yoon, W. H. Yeo, T. Lee, S. M. Won, Y. Jung, Y. J. Heo, K. J. Yu, Sci. Adv. 2023, 9, eadh1765.

[43] J. Man, Y. Shen, Y. Song, K. Yang, P. Pei, L. Hu, J. Contr. Release 2024, 370, 318.

[44] J. Liu, L. Shi, Y. Wang, M. Li, C. Zhou, L. Zhang, C. Yao, Y. Yuan, D. Fu, Y. Deng, M. Liu, G. Wang, L. Wang, Z. Wang, Nano Today 2022, 47, 101627.

[45] H. Sies, V. V. Belousov, N. S. Chandel, M. J. Davies, D. P. Jones, G. E. Mann, M. P. Murphy, M. Yamamoto, C. Winterbourn, Nat. Rev. Mol. Cell Biol. 2022, 23, 499.

[46] H. Byun, Y. Han, E. Kim, I. Jun, J. Lee, H. Jeong, S. J. Huh, J. Joo, S. R. Shin, H. Shin, Bioact. Mater. 2024, 36, 185.

[47] H. Maldonado, B. D. Savage, H. R. Barker, U. May, M. Vähätupa, R. K. Badiani, K. I. Wolanska, C. M. J. Turner, T. Pemmari, T. Ketomäki, S. Prince, M. J. Humphries, E. Ruoslahti, M. R. Morgan, T. A. H. Järvinen, Nat. Commun. 2023, 14, 8069.

[48] J. Zhang, Y. Zhu, Y. Zhang, W. Lin, J. Ke, J. Liu, L. Zhang, J. Liu, Mater. Sci. Eng. C 2021, 131, 112538.

[49] Y. Hu, Y. Miao, Y. Zhang, X. Wang, X. Liu, W. Zhang, D. Deng, ACS Nano 2024, 18, 27557.

[50] J. Zhang, C. M. Simpson, J. Berner, H. B. Chong, J. Fang, Z. Ordulu, T. Weiss-Sadan, A. P. Possemato, S. Harry, M. Takahashi, T.-y. Yang, M. Richter, H. Patel, A. E. Smith, A. D. Carlin, A. F. Hubertus de Groot, K. Wolf, L. Shi, T.-Y. Wei, B. R. Dürr, N. J. Chen, T. Vornbäumen, N. O. Wichmann, M. S. Mahamdeh, V. Pooladanda, Y. Matoba, S. Kumar, E. Kim, S. Bouberhan, E. Oliva, B. R. Rueda, R. J. Soberman, N. Bardeesy, B. B. Liau, M. Lawrence, M. P. Stokes, S. A. Beausoleil, L. Bar-Peled, Cell 2023, 186, 2361.

[51] M. Rodrigues, N. Kosaric, C. A. Bonham, G. C. Gurtner, Physiol. Rev. 2019, 99, 665.

[52] S. Willenborg, D. E. Sanin, A. Jais, X. Ding, T. Ulas, J. Nüchel, M. Popović, T. MacVicar, T. Langer, J. L. Schultze, A. Gerbaulet, A. Roers, E. J. Pearce, J. C. Brüning, A. Trifunovic, S. A. Eming, Cell Metab. 2021, 33, 2398.

[53] R. L. Konger, E. Derr-Yellin, T. A. Zimmers, T. Katona, X. Xuei, Y. Liu, H.-M. Zhou, E. R. Simpson, M. J. Turner, Int. J. Mol. Sci. 2021, 22, 8634.

[54] A. Magadum, F. B. Engel, Int. J. Mol. Sci. 2018, 19, 2013.

[55] J. Zhong, X. He, X. Gao, Q. Liu, Y. Zhao, Y. Hong, W. Zhu, J. Yan, Y. Li, Y. Li, N. Zheng, Y. Bao, H. Wang, J. Ma, W. Huang, Z. Liu, Y. Lyu, X. Ke, W. Jia, C. Xie, Y. Hu, L. Sheng, H. Li, Nat. Commun. 2023, 14, 5451.

[56] X. Zhang, M. Mao, Z. Zuo, Diabetes, Metab. Syndrome Obes. Targets Ther. 2022, 15, 2287.

RIGHTS & PERMISSIONS

2025 The Author(s). Interdisciplinary Medicine published by Wiley-VCH GmbH on behalf of Nanfang Hospital, Southern Medical University.