Co-Delivery of Ferrostatin-1 and M2 Macrophage-Derived Exosomal Signals via Engineered Hybrid Nanovesicles Enables Synergistic Neuroprotection in Traumatic Brain Injury.

Secondary brain injury after traumatic brain injury (TBI) is driven largely by ferroptosis-induced neuronal death and maladaptive neuroinflammation. Current therapies are limited by poor drug delivery and the narrow scope of single-pathway interventions. Here, we report a biomimetic hybrid nanovesicle (hMLV) engineered to codeliver the ferroptosis inhibitor ferrostatin-1 (Fer-1) and M2 macrophage-derived exosomes, enabling simultaneous suppression of neuronal ferroptosis and reprogramming of the immune microenvironment. The liposomal core encapsulates hydrophobic Fer-1 to enhance solubility and stability, while the exosomal membrane promotes blood-brain barrier penetration, lesion targeting via chemokine receptors, and immune evasion through CD47 expression. Within injured brain tissue, released Fer-1 restores glutathione peroxidase 4 (GPX4) activity, reduces lipid peroxidation, and prevents ferroptotic neuronal death. Concurrently, exosomal cytokines such as interleukin-10 and transforming growth factor-β drive macrophage polarization toward a reparative M2 phenotype, mitigating neuroinflammation. This dual mechanism establishes a positive therapeutic cycle: ferroptosis inhibition dampens inflammatory triggers, while M2 polarization reduces oxidative stress. In a murine TBI model, hMLV treatment conferred superior neuroprotection and functional recovery compared with monotherapies. These findings highlight hMLV as a clinically translatable nanoplatform for synergistic, mechanism-guided intervention in secondary brain injury.