Injectable ECM-mimetic dynamic hydrogels abolish ferroptosis-induced post-discectomy herniation through in-situ delivery of nucleus pulposus progenitor cell-derived exosomes [miRNA-Seq]
The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then 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 enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential. Overall design: miRNA sequencing analysis performed on nucleus pulposus progenitor cell-derived exosomes and nucleus pulposus cell-derived exosomes.