A let-7a-5p-engineered extracellular vesicle-laden bioactive scaffold promotes immunomodulation and regeneration of segmental tracheal defects.
- 1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
- 2State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
- 3Department of Anesthesiology, The 986th Hospital of Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Abstract
Segmental tracheal defects resulting from trauma, tumor resection, or congenital malformations pose significant challenges for reconstruction. Persistent post-injury inflammation, inadequate neovascularization, and delayed epithelial restoration contribute to the formation of granulation tissue and subsequent graft failure. In this study, we developed a bioactive tracheal scaffold for sustained local delivery of let-7a-5p-engineered extracellular vesicles (let-7a-5p-EVs) to modulate the regenerative microenvironment during tracheal repair. The scaffold was constructed by integrating a mechanically optimized polycaprolactone (PCL) framework with a 20% Pluronic F127 hydrogel, which served as a local reservoir for EV retention and sustained release. Let-7a-5p-EVs were generated from lentivirally engineered human gingiva-derived mesenchymal stem cells and showed typical EV morphology, representative EV marker expression, and efficient uptake by airway epithelial cells. In vitro, let-7a-5p-EVs enhanced airway epithelial cell migration and shifted lipopolysaccharide (LPS)-induced macrophages from a pro-inflammatory M1-like phenotype toward a reparative M2-like phenotype, accompanied by reduced inflammatory cytokine expression. In a rabbit segmental tracheal defect model, the let-7a-5p-EV-laden scaffold enhanced neovascularization, mitigated local inflammatory responses, promoted mucociliary epithelial reconstruction, and maintained airway patency. The let-7a-5p-EV scaffold improved biomechanical recovery, and increased survival rates. Transcriptomic profiling and molecular validation indicated that these effects were associated with the attenuation of nuclear factor kappa B (NF-κB)-associated inflammatory activation, as evidenced by reduced p65 phosphorylation and nuclear localization. These findings demonstrate that sustained local delivery of engineered EVs from a mechanically competent bioactive scaffold provides an effective immunomodulatory strategy for the regenerative repair of segmental tracheal defects and offers translational potential for functional airway reconstruction.
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BibTeX
@article{liu2026let7a5pengineered,
title = {{A let-7a-5p-engineered extracellular vesicle-laden bioactive scaffold promotes immunomodulation and regeneration of segmental tracheal defects.}},
author = {Bing Liu and Na Wei and Lirong Liang and Zhiqiang Shi and Ping Liu and Tian Zeng and Haopeng Zhang and Hui Zhang},
journal = {Bioactive materials},
year = {2026},
month = oct,
doi = {10.1016/j.bioactmat.2026.10.008},
url = {https://europepmc.org/article/MED/42999915},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A let-7a-5p-engineered extracellular vesicle-laden bioactive scaffold promotes immunomodulation and regeneration of segmental tracheal defects.
AU - Bing Liu
AU - Na Wei
AU - Lirong Liang
AU - Zhiqiang Shi
AU - Ping Liu
AU - Tian Zeng
AU - Haopeng Zhang
AU - Hui Zhang
PY - 2026
DA - 2026/10/30
JO - Bioactive materials
DO - 10.1016/j.bioactmat.2026.10.008
UR - https://europepmc.org/article/MED/42999915
AB - Segmental tracheal defects resulting from trauma, tumor resection, or congenital malformations pose significant challenges for reconstruction. Persistent post-injury inflammation, inadequate neovascularization, and delayed epithelial restoration contribute to the formation of granulation tissue and subsequent graft failure. In this study, we developed a bioactive tracheal scaffold for sustained local delivery of let-7a-5p-engineered extracellular vesicles (let-7a-5p-EVs) to modulate the regenerative microenvironment during tracheal repair. The scaffold was constructed by integrating a mechanically optimized polycaprolactone (PCL) framework with a 20% Pluronic F127 hydrogel, which served as a local reservoir for EV retention and sustained release. Let-7a-5p-EVs were generated from lentivirally engineered human gingiva-derived mesenchymal stem cells and showed typical EV morphology, representative EV marker expression, and efficient uptake by airway epithelial cells. In vitro, let-7a-5p-EVs enhanced airway epithelial cell migration and shifted lipopolysaccharide (LPS)-induced macrophages from a pro-inflammatory M1-like phenotype toward a reparative M2-like phenotype, accompanied by reduced inflammatory cytokine expression. In a rabbit segmental tracheal defect model, the let-7a-5p-EV-laden scaffold enhanced neovascularization, mitigated local inflammatory responses, promoted mucociliary epithelial reconstruction, and maintained airway patency. The let-7a-5p-EV scaffold improved biomechanical recovery, and increased survival rates. Transcriptomic profiling and molecular validation indicated that these effects were associated with the attenuation of nuclear factor kappa B (NF-κB)-associated inflammatory activation, as evidenced by reduced p65 phosphorylation and nuclear localization. These findings demonstrate that sustained local delivery of engineered EVs from a mechanically competent bioactive scaffold provides an effective immunomodulatory strategy for the regenerative repair of segmental tracheal defects and offers translational potential for functional airway reconstruction.
SN - 2452-199X
ER -