Targeted delivery of the GPX4 activator via HUCMSC-derived exosomes inhibits ferroptosis in spinal cord injury.

Spinal cord injury (SCI) is a severe and multifaceted neurological trauma characterized by neuronal loss, axonal disruption, and limited regenerative potential, often causing lasting neurological deficits. Ferroptosis promotes neural cell death following SCI. The activation of glutathione peroxidase 4 (GPX4) to inhibit ferroptosis is a promising strategy to repair the injured spinal cord. The efficacy of existing treatments is limited due to their inability to penetrate the blood‒spinal cord barrier (BSCB). To address this challenge, we developed a multifunctional delivery system based on human umbilical cord mesenchymal stromal cell-derived exosomes (MSC-EXOs) targeting the spinal cord. These exosomes were modified with the transactivator of transcription peptide (TAT) and neuron-targeting peptide (RVG) to increase BSCB penetration and SCI-targeting specificity and were also being loaded with the GPX4 activator (GA) to enable ferroptosis inhibition. This multifunctional exosome system has the ability to reduce lipid peroxidation through the activation of GPX4, modulate iron homeostasis, mitigate inflammation, and effectively target the ferroptosis pathway. This targeted approach protects neuronal cells from ferroptosis, promotes axon regeneration and reduce neuroinflammation. This study introduces an innovative, exosome-based strategy to mitigate ferroptosis, underscoring its translational potential for SCI and expanding the possibilities for neuroregeneration. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-025-03755-7.