A Conjugation Delivery System of Macrophages and Platelet Pharmacytes Promotes Regeneration After Spinal Cord Injury

Mitochondrial dysfunction occurs in macrophages with efferocytosis defects, which hinders recovery from tissue injury. Targeting intercellular mitochondrial transfer is a promising therapy for augmenting cellular therapy. Here, this work elucidates the stress resistance capabilities of mitochondria in anucleate platelets and shows that platelets transfer mitochondria to macrophages under cellular stress, which restores impaired efferocytosis. This work devises a delivery system in which platelets are loaded with cationic polymers (NPs) for PPARγ overexpression and conjugated to macrophages (M-P-NPs@PPARγ). In this system, activated platelets induce mitochondrial transfer and release NPs into macrophages, increasing ATP production and maintaining lipid homeostasis. As a proof-of-concept, in representative efferocytosis-deficit central nervous system disease spinal cord injury model, impaired efferocytosis is reversed by M-P-NP@PPARγ, resulting in neural regeneration and remyelination and ultimately promoting motor function recovery. In summary, this work has developed a strategy combining mitochondria and gene delivery to restore macrophage efferocytosis postinjury by regulating energy and lipid metabolism.