Targeted blood-brain barrier penetration for traumatic brain injury therapy via RXR/PPAR-driven microglial M2 polarization.

As a leading global cause of death and disability, traumatic brain injury (TBI) triggers a complex secondary injury process leading to long-term neurological impairment. Current therapeutic efficacy is limited by the blood-brain barrier (BBB) and the absence of integrated approaches to address neuroinflammation and neuroregeneration. We designed a biomimetic nanomedicine (Ali-NPs@Mexo) by encapsulating alitretinoin(Ali)-loaded albumin nanospheres within mesenchymal stromal cell (MSC)-derived exosomal membranes. This platform exploits the natural BBB-crossing and inflammation-targeting capabilities of exosomes to enhance localized drug delivery. Mechanistic studies revealed that Ali-NPs@Mexo triggers RXR/PPAR signaling to promote M1-to-M2 microglial polarization, thereby mitigating acute inflammation. Moreover, it protects neurons by inhibiting reactive astrogliosis and supporting the growth of neural stem cells and oligodendrocytes. In vivo, Ali-NPs@Mexo significantly improved functional and cognitive outcomes in mice. This integrated strategy of targeted immune-modulation and neuro-regeneration provides a translatable framework for effective TBI intervention.