2. Academic Validation
  3. Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells

Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells

  • J Nanobiotechnology. 2023 Nov 29;21(1):455. doi: 10.1186/s12951-023-02185-7.
Liwen Luo # 1,  Hongyu Zhang # 2,  Shiyu Zhang # 1,  Chengqin Luo # 2,  Xuewei Kan 3,  Jun Lv 4,  Ping Zhao 5,  Zhiqiang Tian 6 7,  Changqing Li 8
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Xinqiao Hospital, Army Medical University (Third Military Medical University), 83, Xinqiao St, Shapingba District, Chongqing, 400037, China.
  • 2 Department of Emergency, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Dermatology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 4 Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
  • 5 State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University, 2, Tiansheng Road, Beibei District, Chongqing, 400715, China. [email protected].
  • 6 Institute of Immunology, PLA, Army Medical University (Third Military Medical University), 30 Gaotanyan St, Shapingba District, Chongqing, 400038, China. [email protected].
  • 7 State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University, 2, Tiansheng Road, Beibei District, Chongqing, 400715, China. [email protected].
  • 8 Department of Orthopaedics, Xinqiao Hospital, Army Medical University (Third Military Medical University), 83, Xinqiao St, Shapingba District, Chongqing, 400037, China. [email protected].
  • # Contributed equally.
PMID: 38017428 DOI: 10.1186/s12951-023-02185-7
Abstract

Background: Reduced supplies of oxygen and nutrients caused by vascular injury lead to difficult-to-heal pressure ulcers (PU) in clinical practice. Rapid vascular repair in the skin wound is the key to the resolution of this challenge, but clinical measures are still limited. We described the beneficial effects of extracellular vesicle-derived silk fibroin nanoparticles (NPs) loaded with milk fat globule EGF factor 8 (MFGE8) on accelerating skin blood vessel and PU healing by targeting CD13 in the vascular endothelial cells (VECs).

Methods: CD13, the specific targeting protein of NGR, and MFGE8, an inhibitor of Ferroptosis, were detected in VECs and PU tissues. Then, NPs were synthesized via silk fibroin, and MFGE8-coated NPs (NPs@MFGE8) were assembled via loading purified protein MFGE8 produced by Chinese hamster ovary cells. Lentivirus was used to over-express MFGE8 in VECs and obtained MFGE8-engineered extracellular vesicles (EVs-MFGE8) secreted by these VECs. The inhibitory effect of EVs-MFGE8 or NPs@MFGE8 on Ferroptosis was detected in vitro. The NGR peptide cross-linked with NPs@MFGE8 was assembled into NGR-NPs@MFGE8. Collagen and silk fibroin were used to synthesize the silk fibroin/collagen hydrogel. After being loaded with NGR-NPs@MFGE8, silk fibroin/collagen hydrogel sustained-release carrier was synthesized to investigate the repair effect on PU in vivo.

Results: MFGE8 was decreased, and CD13 was increased in PU tissues. Similar to the effect of EVs-MFGE8 on inhibiting Ferroptosis, NPs@MFGE8 could inhibit the mitochondrial autophagy-induced Ferroptosis of VECs. Compared with the hydrogels loaded with NPs or NPs@MFGE8, the hydrogels loaded with NGR-NPs@MFGE8 consistently released NGR-NPs@MFGE8 targeting CD13 in VECs, thereby inhibiting mitochondrial Autophagy and Ferroptosis caused by hypoxia and accelerating wound healing effectively in rats.

Conclusions: The silk fibroin/collagen hydrogel sustained-release carrier loaded with NGR-NPs@MFGE8 was of great significance to use as a wound dressing to inhibit the Ferroptosis of VECs by targeting CD13 in PU tissues, preventing PU formation and promoting wound healing.

Keywords

Extracellular vesicles; MFGE8; Pressure ulcers; Silk fibroin nanoparticles; Vascular endothelial cells.

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