Dual-Gene Edited Extracellular Vesicles Remodel the Redox Homeostasis to Inhibit Ferroptosis in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is driven by ferroptosis of nucleus pulposus cells (NPCs) as a core pathological mechanism. Nucleus pulposus progenitor cells (NPPCs), exhibiting stem cell-like properties, yield extracellular vesicles (PEVs) with high affinity for NPCs and enable targeted phenotypic regulation. However, natural PEVs possess limited bioactivity. Therefore, we constructed engineered mFD-PEVs modified with FTH1 and DAB2. In vitro experiments demonstrated that mFD-PEVs efficiently deliver FTH1, maintained SLC7A11/GPX4-associated redox defense, suppress NPCs oxidative stress, and attenuate ferroptosis. Furthermore, in vivo studies confirmed the potent therapeutic efficacy of mFD-PEVs in promoting intervertebral disc regeneration. Transcriptomic analysis further revealed that mFD-PEVs predominantly modulate molecular pathways associated with ferroptosis and oxidative stress. In summary, the gene-edited mFD-PEVs reprogram redox homeostasis in NPCs, regulate ferroptosis, and promote intervertebral disc regeneration.