An inflammation-targeted lipid nanoparticle inhibiting ferroptosis for spinal cord injury repair.

Erythropoietin (EPO) has been considered as a potentially effective drug candidate for the treatment of spinal cord injury (SCI). However, due to insufficient drug accumulation in the lesion site and systemic off-target effects, the clinical translation of EPO is limited. To overcome these limitations, we rationally designed a mannose-modified lipid nanoparticle (MLNP) system as a bioresponsive nanocarrier for targeted delivery of EPO mRNA to CD206-enriched inflammatory macrophages/microglia within the injured spinal cord. The engineered EPO@MLNPs exhibited well-defined physicochemical properties, high mRNA encapsulation efficiency, and enhanced stability, enabling preferential accumulation at the SCI lesion and sustained local translation of therapeutic EPO protein. In a mouse model of SCI, this materials-enabled delivery strategy effectively attenuated neuroinflammation, reduced neuronal loss, preserved serotonergic axonal integrity, and markedly improved motor functional recovery. Mechanistically, integrated transcriptomic profiling and experimental validation demonstrated that EPO@MLNP treatment suppressed ferroptosis by regulating iron metabolism and lipid peroxidation pathways. Overall, this study presents a targeted mRNA nanotherapeutic strategy that modulates both inflammatory and ferroptotic pathways, providing a promising approach for SCI treatment and other neuroinflammatory disorders.