Engineered lesion-homing liposomes encapsulating Rosuvastatin enhance spinal cord injury repair by preventing the formation of foamy macrophages

Following spinal cord injury (SCI), infiltrating macrophages excessively phagocytose myelin debris, subsequently transforming into foamy macrophages that significantly exacerbate secondary injury pathology. In this study, we developed cysteine-alanine-glutamine-lysine (CAQK) tetrapeptide-modified liposomes (Lip) encapsulating Rosuvastatin (designated as CAQK-Lip-R), specifically engineered for targeted delivery to SCI lesions, to systematically investigate both the therapeutic effects and molecular mechanisms underlying CAQK-Lip-R-mediated inhibition of foamy macrophage formation and promotion of functional recovery after spinal cord injury. The novel-designed CAQK-Lip-R demonstrated efficient accumulation at injury sites and exerted substantial neuroprotective effects, as evidenced by significantly promoted functional recovery in the injured spinal cord. Mechanistically, these therapeutic benefits were achieved through regulation of myelin lipid debris clearance and macrophage polarization conversion via enhanced autophagy initiation and progression, coupled with effective suppression of PI3K/Akt/mTOR signaling axis activity and concomitant augmentation of autophagic flux in macrophages. Our findings not only elucidate a previously unrecognized mechanism of CAQK-Lip-R action in preventing foamy macrophage formation within the injured spinal cord microenvironment, but also present an innovative therapeutic paradigm utilizing a lesion-homing nano-delivery system for SCI treatment.