Excessive accumulation and insufficient clearance of apoptotic cells following spinal cord injury (SCI) are key factors contributing to persistent injury. Macrophage efferocytosis is essential for resolving injury but is compromised by mitochondrial dysfunction and lysosomal overload. Maintaining mitochondrial functional homeostasis is therefore crucial for preserving the acidic lysosomal environment, alleviating the cellular lysosomal burden, and sustaining efferocytosis. Common mitochondrial quality control (MQC) pathways such as mitophagy increase the lysosomal burden. Here, we investigated how polo-like kinase 1 (PLK1) regulates macrophage efferocytosis and elucidated the underlying mechanism of migrasome-mediated mitocytosis. We demonstrate that PLK1 regulates TSPAN4-dependent migrasome formation, which drives the selective extrusion of damaged mitochondria, alleviates the lysosomal burden, and increases efferocytic capacity. To enable targeted PLK1 delivery, we engineered macrophage membrane-coated, reactive oxygen species (ROS)-responsive nanocomplexes encapsulating PLK1 plasmids (MM-NPs@PLK1). This biomimetic nanoplatform preferentially accumulates in the injured spinal cord, promotes macrophage-associated PLK1 delivery, enhances mitocytosis and efferocytosis, supports neural tissue repair, and significantly improves locomotor recovery in SCI mice. In summary, our study reveals a PLK1-regulated MQC mechanism that sustains macrophage efferocytosis through migrasome-mediated mitocytosis, providing a promising therapeutic strategy for SCI.
