Abstract
Spinal cord injury (SCI) is a severe central nervous system disorder characterized by complex neuroinflammatory responses. While natural compounds such as daphnetin have demonstrated anti-inflammatory and neuroprotective effects, their clinical application is hindered by low bioavailability. To address this limitation, we developed a biofabricated nanoliposomal drug delivery system, designed to enhance daphnetin's targeted delivery to macrophages and improve its therapeutic efficacy in SCI repair. A biofabrication-driven approach was employed to synthesize and optimize targeted liposomal nanocarriers (Da@Lip-CRV) using phospholipid-based vesicles conjugated with CRVLRSGSC peptides for macrophage specificity. Their targeting and therapeutic efficiency were evaluated in vitro and in vivo. The biofabricated liposomal system exhibited stable physicochemical properties and enhanced macrophage targeting efficiency. Transcriptomic analyses revealed that Da@Lip-CRV suppressed NF-κB-mediated inflammation, inhibited macrophage pyroptosis, and promoted M2 polarization, thereby facilitating an anti-inflammatory microenvironment conducive to neural repair. Da@Lip-CRV showed superior recovery of hindlimb function, reduced glial scarring, and improved neuronal survival in vivo. This study presents a biofabrication-based liposomal drug delivery platform for targeted SCI therapy. The findings demonstrated that optimize targeted liposomal nanocarriers (Da@Lip-CRV) regulated macrophage polarization and inhibited the pyroptosis of macrophage so as to provide a promising strategy for the clinical treatment of SCI.