Injectable ECM-mimetic dynamic hydrogels abolish ferroptosis-induced post-discectomy herniation through delivering nucleus pulposus progenitor cell-derived exosomes

Wenkai Wang, Zhuo Cheng, Miao Yu, Ke Liu, Hongli Duan, Yang Zhang, Xinle Huang, Menghuan Li, Changqing Li, Yan Hu (), Zhong Luo () and Minghan Liu ()
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Wenkai Wang: Third Military Medical University (Army Medical University)
Zhuo Cheng: Third Military Medical University (Army Medical University)
Miao Yu: Third Military Medical University (Army Medical University)
Ke Liu: Third Military Medical University (Army Medical University)
Hongli Duan: Third Military Medical University (Army Medical University)
Yang Zhang: Third Military Medical University (Army Medical University)
Xinle Huang: Third Military Medical University (Army Medical University)
Menghuan Li: Chongqing University
Changqing Li: Third Military Medical University (Army Medical University)
Yan Hu: Chongqing University
Zhong Luo: Chongqing University
Minghan Liu: Third Military Medical University (Army Medical University)

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Discectomy-induced ferroptosis of nucleus pulposus cells (NPCs) contributes to postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). We discover that nucleus pulposus progenitor cells (NPPCs) could imprint ferroptosis resistance into NPCs through exosome-dependent intercellular transmission of miR-221-3p. Based on these findings, we first develop synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity, which are integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enables marked ferroptosis inhibition in NPCs that not only prevents LDH recurrence but also reverses the IDD symptoms, leading to robust restoration of NP structure and functions. In summary, this study offers a promising approach for treating disc herniation.

Date: 2025
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DOI: 10.1038/s41467-025-58447-5

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