Hierarchical targeting biomimetic nanoparticles directing to lesion site and mitochondria promote neuroregeneration and attenuate inflammation after spinal cord injury.

Following primary spinal cord injury (SCI), mitochondrial dysfunction induces oxidative stress, which in turn exacerbates secondary injury, including neuronal loss and the formation of an inhibitory microenvironment. To intervene in this pathological cascade, we constructed a hierarchically targeted biomimetic nanomedicine (MM@DHM) designed for sequential delivery to the lesion site and subsequently to mitochondria. Macrophage membrane coating mediates first-stage targeting to the injured spinal cord, while triphenylphosphonium (TPP) modification directs second-stage accumulation within mitochondria of lesional cells, enabling precise delivery of the SIRT3 agonist dihydromyricetin (DHM) to its site of action. Mechanistically, MM@DHM activates SIRT3, promotes SOD2 deacetylation, and enhances Pink1-Parkin-mediated mitophagy, consequently alleviating oxidative stress and restoring mitochondrial homeostasis. These integrated cellular effects confer robust neuroprotection, attenuate neuroinflammation, and improve functional recovery in a mouse model of SCI. Collectively, this work demonstrates that mitochondrial targeting represents a promising therapeutic strategy for ameliorating oxidative damage and mitochondrial dysfunction in SCI, and underscores the potential of cascade-targeted nanoplatforms for central nervous system repair.