Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertk(hi) bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with the mitochondria, optimizing its targeting affinity for the injury site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated mitochondrial dysfunction, and attenuated pro-inflammatory profiles in macrophages, both in vitro and in vivo. The intravenously delivered mitochondrial compounds targeted the SCI epicenter, with macrophages being the primary recipients. Critically, they promoted tissue regeneration and bolstered functional recovery in SCI mice. This study heralds a transformative approach to mitochondrial transplantation in SCI, spotlighting the modulation of macrophage activity, phagocytosis, and phenotype.