Citation: Zeyu Xu, Ming Zhang, Tangtang He, Zhe Wang, Wenwen Deng, Xia Cao, Qilong Wang, Yiwei Wang, Jun Chen. Controlled shikonin delivery from polycaprolactone scaffolds promotes diabetic wound repair via coordinated inflammation resolution and angiogenesis[J]. Chinese Chemical Letters, ;2026, 37(10): 112130. doi: 10.1016/j.cclet.2025.112130 shu

Controlled shikonin delivery from polycaprolactone scaffolds promotes diabetic wound repair via coordinated inflammation resolution and angiogenesis

Zeyu Xu ^{a, b} ,
Ming Zhang ^{a, b} ,
Tangtang He ^{a, b} ,
Zhe Wang ^c ,
Wenwen Deng ^c ,
Xia Cao ^c ,
Qilong Wang ^c ,
Yiwei Wang ^a ,
Jun Chen ^{a, b, *,}

a.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
b.
Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, China
c.
Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang 212013, China

chenjun75@njucm.edu.cn

Received Date: 13 October 2025
Revised Date: 14 November 2025
Accepted Date: 17 November 2025
Available Online: 19 November 2025

Figures(4)

Chronic diabetic wounds are characterized by persistent inflammation and impaired angiogenesis, presenting a major therapeutic challenge. Here, we report a three-dimensional (3D)-printed polycaprolactone (PCL) scaffold integrating shikonin (SK), a bioactive compound derived from Lithospermum erythrorhizon, to achieve controlled drug release and multifunctional wound repair. The PCL/SK scaffold exhibited a porous, breathable architecture with high mechanical integrity and biocompatibility, enabling sustained SK release over 72 h. In a diabetic mouse wound model, the PCL/SK scaffold significantly accelerated wound closure, enhanced collagen deposition, and increased the density of anti-inflammatory CD206⁺ macrophages compared to free SK or PCL controls. Transcriptomic and immunohistochemical analyses revealed that PCL/SK treatment upregulated angiogenesis-related genes, including vascular endothelial growth factor (Vegf), platelet endothelial cell adhesion molecule 1 (Pecam1) and TEK receptor tyrosine kinase (Tek), meanwhile elevated CD31⁺ and VEGF⁺ endothelial markers, concomitant with improved blood perfusion. Mechanistically, this effect was attributed to synergistic anti-inflammatory and pro-angiogenic modulation by sustained SK delivery and the supportive PCL microenvironment. These findings establish a bioactive drug-biomaterial hybrid platform that leverages controlled release to coordinate immune resolution and vascular regeneration, offering a promising strategy for chronic diabetic wound management and broader regenerative applications.
- Diabetic wound healing,
- Controlled drug release,
- Shikonin delivery,
- 3D-printed scaffold,
- Anti-inflammatory therapy
1. [1]
  D.G. Armstrong, T.W. Tan, A.J.M. Boulton, et al., JAMa 330 (2023) 62–75. doi: 10.1001/jama.2023.10578
2. [2]
  L. Xie, X. Zhang, X. Wang, et al., Chin. Chem. Lett. 36 (2025) 110848. doi: 10.1016/j.cclet.2025.110848
3. [3]
  S.A. Eming, P. Martin, M. Tomic-Canic, Sci. Transl. Med. 6 (2014) 265sr266.
4. [4]
  Y. Hong, Q. Su, X. Wu, et al., Chin. Chem. Lett. 37 (2026) 111846. doi: 10.1016/j.cclet.2025.111846
5. [5]
  J.G. Powers, C. Higham, K. Broussard, et al., J. Am. Acad. Dermatol. 74 (2016) 607–625. doi: 10.1016/j.jaad.2015.08.070
6. [6]
  A.Y.W. Wong, N.M.F. Hooi, B.S.Y. Yeo, et al., J. Clin. Endocrinol. Metab. 109 (2024) e1642–e1651. doi: 10.1210/clinem/dgae128
7. [7]
  Z. Xu, M. Dong, S. Yin, et al., Adv. Drug Deliv. Rev. 195 (2023) 114764. doi: 10.1016/j.addr.2023.114764
8. [8]
  X. Zhou, S. Chen, B. Savitz, et al., Diabetes Obes. Metab. 27 (2025) 3431–3441. doi: 10.1111/dom.16367
9. [9]
  A.E. Louiselle, S.M. Niemiec, C. Zgheib, et al., Transl. Res. 236 (2021) 109–116. doi: 10.1016/j.trsl.2021.05.006
10. [10]
  Y. Li, Z. Zhu, S. Li, et al., J. Nanobiotechnology 22 (2024) 398. doi: 10.1186/s12951-024-02684-1
11. [11]
  M. Sharifiaghdam, E. Shaabani, R. Faridi-Majidi, et al., Mol. Ther. 30 (2022) 2891–2908. doi: 10.1016/j.ymthe.2022.07.016
12. [12]
  M. Rai, A. Yadav, A. Gade, Biotechnol. Adv. 27 (2009) 76–83. doi: 10.1016/j.biotechadv.2008.09.002
13. [13]
  Y. Liang, Q. Li, L. Hu, et al., Chin. Chem. Lett. 35 (2024) 109459. doi: 10.1016/j.cclet.2023.109459
14. [14]
  B. Lu, D. Wang, J. Guo, et al., Chin. Chem. Lett. 36 (2025) 110601. doi: 10.1016/j.cclet.2024.110601
15. [15]
  Y. Liang, J. He, B. Guo, ACS Nano 15 (2021) 12687–12722. doi: 10.1021/acsnano.1c04206
16. [16]
  Z.U. Arif, M.Y. Khalid, R. Noroozi, et al., Int. J. Biol. Macromol. 218 (2022) 930–968. doi: 10.1016/j.ijbiomac.2022.07.140
17. [17]
  J. Xiao, X. Ai, C. Zhou, et al., Chin. Chem. Lett. 37 (2026) 111291. doi: 10.1016/j.cclet.2025.111291
18. [18]
  W. Huang, M. Lv, Z.G. Gao, Chin. Chem. Lett. 22 (2011) 749–752. doi: 10.1016/j.cclet.2010.12.057
19. [19]
  A. Sadeghianmaryan, N. Ahmadian, S. Wheatley, et al., Int. J. Biol. Macromol. 266 (2024) 131207. doi: 10.1016/j.ijbiomac.2024.131207
20. [20]
  C. Ding, J. Yang, N. Wang, et al., Int. J. Biol. Macromol. 262 (2024) 129937. doi: 10.1016/j.ijbiomac.2024.129937
21. [21]
  C. Xue, J. Dou, S. Zhang, et al., J. Gene Med. 26 (2024) e3633. doi: 10.1002/jgm.3633
22. [22]
  J. He, J. Incl. Phenom. Macrocycl. Chem. 63 (2008) 249–255. doi: 10.1007/978-3-540-69209-6_14
23. [23]
  N. Joy, D. Venugopal, S. Samavedi, Eur. Polym. J. 168 (2022) 111102. doi: 10.1016/j.eurpolymj.2022.111102
24. [24]
  C. Guo, J. He, X. Song, et al., Pharmacol. Res. 149 (2019) 104463. doi: 10.1016/j.phrs.2019.104463
25. [25]
  S. Sharma, V.K. Rai, R.K. Narang, et al., Life Sci. 290 (2022) 120096. doi: 10.1016/j.lfs.2021.120096
26. [26]
  B. Fuchs, S. Mert, D. Hofmann, et al., J. Tissue Eng. 16 (2025) 20417314251317542. doi: 10.1177/20417314251317542
27. [27]
  G. Mao, S. Tian, Y. Shi, et al., Carbohydr. Polym. 311 (2023) 120757.
28. [28]
  L. Liu, X. Hao, J. Zhang, et al., Stem Cell Res. Ther. 15 (2024) 437.
29. [29]
  Y. Luo, X. Yi, T. Liang, et al., Stem Cell Res. Ther. 10 (2019) 279. doi: 10.1186/s13287-019-1389-4
30. [30]
  Y. Hu, R. Tao, L. Chen, et al., J. Nanobiotechnology 19 (2021) 150.
31. [31]
  Z. Xu, G. Liu, P. Liu, et al., Acta Biomater. 147 (2022) 147–157.
32. [32]
  S. Li, J. Sun, J. Yang, et al., Biomater. Res. 27 (2023) 11.
33. [33]
  C.H. Su, W.P. Li, L.C. Tsao, et al., ACS Nano 13 (2019) 4290–4301. doi: 10.1021/acsnano.8b09417
34. [34]
  Y. Guo, M. Zhou, Z. Mu, et al., Biomed. Pharmacother. 165 (2023) 115138.
35. [35]
  T. Dong, R. Li, Z. Lu, et al., Int. J. Biol. Macromol. 318 (2025) 144844.
36. [36]
  S. Harmanci, A. Dutta, S. Cesur, et al., Polymers 14 (2022) 5306. doi: 10.3390/polym14235306
37. [37]
  M. Ayran, A.Y. Dirican, E. Saatcioglu, et al., Bioengineering 9 (2022) 427. doi: 10.3390/bioengineering9090427
38. [38]
  M. Mehdikhani, P.Y. Huri, S.A. Poursamar, et al., Int. J. Biol. Macromol. 282 (2024) 136692.
39. [39]
  E.S. Rezaei, S.A. Poursamar, M. Naeimi, et al., Int. J. Biol. Macromol. 269 (2024) 131859.
40. [40]
  Y. Song, Q. Hu, S. Liu, et al., Int. J. Biol. Macromol. 275 (2024) 129705.
41. [41]
  Z. Xu, L. Zhang, Q. Tang, et al., Acta Pharm. Sin. B 15 (2025) 611–626.
42. [42]
  Y. Song, Q. Ding, Y. Hao, et al., Molecules 28 (2023) 7950. doi: 10.3390/molecules28247950
43. [43]
  S.A. Eming, T.A. Wynn, P. Martin, Science 356 (2017) 1026–1030. doi: 10.1126/science.aam7928
44. [44]
  Z. Muwaffak, A. Goyanes, V. Clark, et al., Int. J. Pharm. 527 (2017) 161–170.
45. [45]
  Z. Liu, X. Chen, C. Li, Biomed. Mater. 17 (2022) 055008. doi: 10.1088/1748-605x/ac8130
46. [46]
  W.S. Choi, J.H. Kim, C.B. Ahn, et al., Polymers 13 (2021) 2584. doi: 10.3390/polym13162584
1. [1]
  Jiajia Wang , XinXin Ge , Yajing Xiang , Xiaoliang Qi , Ying Li , Hangbin Xu , Erya Cai , Chaofan Zhang , Yulong Lan , Xiaojing Chen , Yizuo Shi , Zhangping Li , Jianliang Shen . An ionic liquid functionalized sericin hydrogel for drug-resistant bacteria-infected diabetic wound healing. Chinese Chemical Letters, 2025, 36(2): 109819-. doi: 10.1016/j.cclet.2024.109819
2. [2]
  Peizhe Li , Qiaoling Liu , Mengyu Pei , Yuci Gan , Yan Gong , Chuchen Gong , Pei Wang , Mingsong Wang , Xiansong Wang , Da-Peng Yang , Bo Liang , Guangyu Ji . Chlorogenic acid supported strontium polyphenol networks ensemble microneedle patch to promote diabetic wound healing. Chinese Chemical Letters, 2024, 35(8): 109457-. doi: 10.1016/j.cclet.2023.109457
3. [3]
  Lina Xie , Xiaohe Zhang , Xiaobo Wang , Zhen Zhang , Tianqi Nie , Jun Wu , Xiaojun Xu . Multifunctional GelMA hydrogel doped with spermidine-ferrocene polymeric nanoparticles for accelerative diabetic wound healing. Chinese Chemical Letters, 2025, 36(11): 110848-. doi: 10.1016/j.cclet.2025.110848
4. [4]
  Huijuan Luo , Haiyue Zuo , Jianzhong Zhu , Juanjuan Zhao , Roufen Chen , Xinle Yang , Fangqi Cao , Ruohan Lou , Xiaowu Dong , Yangyang Bian , Ligen Lin . Computer-aided discovery of peptidyl arginine deiminase 4 inhibitors to suppress NETosis and accelerate diabetic wound healing. Chinese Chemical Letters, 2026, 37(6): 111510-. doi: 10.1016/j.cclet.2025.111510
5. [5]
  Yue Sun , Yingnan Zhu , Jiahang Si , Ruikang Zhang , Yalan Ji , Jinjie Fan , Yuze Dong . Glucose-activated nanozyme hydrogels for microenvironment modulation via cascade reaction in diabetic wound. Chinese Chemical Letters, 2025, 36(4): 110012-. doi: 10.1016/j.cclet.2024.110012
6. [6]
  Chenshi Lin , Chao Teng , Bingbing Li , Wei He . Anti-inflammatory drug-assisted microRNA gene therapy for effectively improving pulmonary hemodynamics. Chinese Chemical Letters, 2025, 36(7): 110450-. doi: 10.1016/j.cclet.2024.110450
7. [7]
  Wenjia Wang , Xingyue He , Xiaojie Wang , Tiantian Zhao , Osamu Muraoka , Genzoh Tanabe , Weijia Xie , Tianjiao Zhou , Lei Xing , Qingri Jin , Hulin Jiang . Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin (Ⅳ) prodrug delivery and enhanced colorectal cancer therapy. Chinese Chemical Letters, 2024, 35(4): 108656-. doi: 10.1016/j.cclet.2023.108656
8. [8]
  Haijun Shen , Yi Qiao , Chun Zhang , Yane Ma , Jialing Chen , Yingying Cao , Wenna Zheng . A matrix metalloproteinase-sensitive hydrogel combined with photothermal therapy for transdermal delivery of deferoxamine to accelerate diabetic pressure ulcer healing. Chinese Chemical Letters, 2024, 35(12): 110283-. doi: 10.1016/j.cclet.2024.110283
9. [9]
  Jia Lin , Le Ding , Yingting Wu , Haoyang Li , Yi Wu , Chen Li , Quangang Zhu , Zhongjian Chen , Xiaoyan Cui , Ting Wang . Photoactivatable hydrogen sulfide donors for visualizing H₂S controlled release in accelerated chronic wound healing. Chinese Chemical Letters, 2026, 37(10): 112100-. doi: 10.1016/j.cclet.2025.112100
10. [10]
  Xiongbo Song , Jinwen Xiao , Juan Wu , Li Sun , Long Chen . Decellularized amniotic membrane promotes the anti-inflammatory response of macrophages via PI3K/AKT/HIF-1α pathway. Chinese Chemical Letters, 2025, 36(1): 109844-. doi: 10.1016/j.cclet.2024.109844
11. [11]
  Yixia Zhang , Caili Xue , Yunpeng Zhang , Qi Zhang , Kai Zhang , Yulin Liu , Zhaohui Shan , Wu Qiu , Gang Chen , Na Li , Hulin Zhang , Jiang Zhao , Da-Peng Yang . Cocktail effect of ionic patch driven by triboelectric nanogenerator for diabetic wound healing. Chinese Chemical Letters, 2024, 35(8): 109196-. doi: 10.1016/j.cclet.2023.109196
12. [12]
  Changyuan Bao , Yunpeng Jiang , Haoyin Zhong , Huaizheng Ren , Junhui Wang , Binbin Liu , Qi Zhao , Fan Jin , Yan Meng Chong , Jianguo Sun , Fei Wang , Bo Wang , Ximeng Liu , Dianlong Wang , John Wang . Synergizing 3D-printed structure and sodiophilic interface enables highly efficient sodium metal anodes. Chinese Chemical Letters, 2024, 35(11): 109353-. doi: 10.1016/j.cclet.2023.109353
13. [13]
  Kaihang Sheng , Yanshuai Wang , Siyuan Yin , Xiuling Li , Xinya Zhang , Xiaowei Li , Dechao Niu . Gold nanorods-loaded quaternized mesoporous silica nanospheres with synergistic adhesion and photothermal antibacterial mechanism for diabetic wound healing. Chinese Chemical Letters, 2026, 37(8): 111852-. doi: 10.1016/j.cclet.2025.111852
14. [14]
  Lele Meng , Ruhe Zhang , Liying Wang , Yuanzheng Wang , Bo Li , Long Chen . Glucose/ROS dual-responsive hydrogel loaded with mangiferin accelerates diabetic wound healing. Chinese Chemical Letters, 2026, 37(9): 111981-. doi: 10.1016/j.cclet.2025.111981
15. [15]
  Yunfen Gao , Liying Wang , Chufan Zhou , Yi Zhao , Hai Huang , Jun Wu . Low-dimensional antimicrobial nanomaterials in anti-infection treatment and wound healing. Chinese Chemical Letters, 2025, 36(3): 110028-. doi: 10.1016/j.cclet.2024.110028
16. [16]
  Yuan Yang , Xiaoli Wu , Hanshuang Li , Yurong Deng , Chengbin Zheng . Determination of selenite and organoselenium in water using GC coupled with a 3D-printed point discharge atomic emission detector and HS-SPME. Chinese Chemical Letters, 2026, 37(8): 112298-. doi: 10.1016/j.cclet.2025.112298
17. [17]
  Yueying Wang , Jianming Xiong , Linwei Xin , Yuanyuan Li , He Huang , Wenjun Miao . Photosensitizer-synergized g-carbon nitride nanosheets with enhanced photocatalytic activity for eradicating drug-resistant bacteria and promoting wound healing. Chinese Chemical Letters, 2025, 36(4): 110003-. doi: 10.1016/j.cclet.2024.110003
18. [18]
  Jing Feng , Yanhong Liu , Liming Gong , Chenfei Liu , Congcong Xiao , Liqing Chen , Mingji Jin , Zhonggao Gao , Wei Huang , Yubo Li . Recent progress on drug delivery systems of regulating intratumoral bacteria for tumor therapy. Chinese Chemical Letters, 2025, 36(11): 110907-. doi: 10.1016/j.cclet.2025.110907
19. [19]
  Yan Yu , Cailing Gan , Kun Shi , Zhongwu Bei , Yang Yu , Meng Pan , Hanzhi Deng , Zhiyong Qian . Recent advances in drug delivery systems for pulmonary fibrosis therapy. Chinese Chemical Letters, 2026, 37(1): 111596-. doi: 10.1016/j.cclet.2025.111596
20. [20]
  Yiyao Wan , Wen Chen , Yan Yu , Meng Pan , Kun Shi , Zhiyong Qian . Biomaterial-based drug delivery systems for the therapy of malignant pleural effusion. Chinese Chemical Letters, 2026, 37(1): 111513-. doi: 10.1016/j.cclet.2025.111513

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(4)
HTML views(0)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142