Neonatal small extracellular vesicle-loaded GelNB hydrogel reprograms the vascular-immune microenvironment for spinal cord injury repair

Feifei Yuan; Chaoran Shi; Xisong Liang; Jiaqi Xu; Yiming Qin; Sheng Xu; Yong Chen; Tian Qin; Yinghe Ding; Zhiyu Hu; Chengjun Li; Hongbin Lu; Jianzhong Hu; Yong Cao

doi:10.1016/j.bioactmat.2026.04.026

Neonatal small extracellular vesicle-loaded GelNB hydrogel reprograms the vascular-immune microenvironment for spinal cord injury repair

Bioact Mater. 2026 May 6:63:953-974. doi: 10.1016/j.bioactmat.2026.04.026. eCollection 2026 Sep.

Authors

Feifei Yuan^{1

2

3}, Chaoran Shi^{1

2

4}, Xisong Liang⁵, Jiaqi Xu^{1

2

3

5}, Yiming Qin^{1

2

3}, Sheng Xu^{1

2

3}, Yong Chen^{2

3

6}, Tian Qin^{1

2

3}, Yinghe Ding^{1

2

3}, Zhiyu Hu^{1

2

3}, Chengjun Li^{2

3

6}, Hongbin Lu^{2

3

6}, Jianzhong Hu^{1

2

3}, Yong Cao^{1

2

3}

Affiliations

¹ Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
² Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
⁶ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Adult mammals with spinal cord injury (SCI) face permanent disability from failed regeneration and scarring, while neonatal mice achieve scarless repair. We show neonatal mouse circulating blood-derived small extracellular vesicles (NCE) rejuvenate adult spinal cord microvascular endothelial cells (SCMECs), restoring lipid metabolism, easing immune imbalance, and supporting neuroaxonal regrowth. Post-SCI myelin debris triggers IRS1-mediated PI3K-Akt-mTOR overactivation in SCMECs, causing harmful lipid droplet buildup, organelle dysfunction, and endothelial-to-mesenchymal transition (EndoMT). It also increases CXCL12 secretion from SCMECs, which recruits CXCR4⁺ macrophages. These macrophages release TNF-α and GDF15, promoting neuronal injury and EndoMT, and forming a destructive feedback loop. We create a "Microenvironment-Reprogramming Potent Hydrogel" - a high-adhesion GelNB hydrogel loaded with NCE - as an efficient delivery tool. NCE targetedly deliver miR-487b-3p to block IRS1 and CXCL12, breaking the vicious cycle. This remodels microvasculature, normalizes SCMEC lipid metabolism, reduces macrophage infiltration, promotes neuroregeneration, and achieves functional recovery. Our study uncovers an endothelium-immune crosstalk axis hindering SCI repair and highlights miR-487b-3p-rich sEVs as a promising therapy.

Keywords: Adult mice; CXCL12-CXCR4; EndoMT; GelNB; IRS1-PI3K-Akt-mTOR; LDs; Lipid metabolism; Microenvironment-reprogramming potent hydrogel; Neonatal mice; Small extracellular vesicles; miR-487b-3p.