Macrophage membrane-mediated targeted drug delivery for treatment of spinal cord injury regardless of the macrophage polarization states

Abstract

Targeted delivery of therapeutics for spinal cord injury (SCI) has been a long-term challenge due to the complexity of the pathological procession. Macrophage, as an immune cell, can selectively accumulate at the trauma site after SCI. This intrinsic targeting, coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI. Worth mentioning, macrophages have multiple polarization states, which may not be ignored when designing macrophage-based delivery systems. Herein, we fabricated macrophage membrane-camouflaged liposomes (RM-LIPs) and evaluated their abilities to extend drug circulation time and target the injured spinal cord. Specially, we detected the expression levels of the two main targeted receptors Mac-1 and integrin α4 in three macrophage subtypes, including unactivated (M0) macrophages, classically activated (M1) macrophages and alternatively activated (M2) macrophages, and compared targeting of these macrophage membrane-coated nanoparticles for SCI. The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro. RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo. Besides, RM-LIPs loaded with minocycline (RM-LIP/MC) showed a comprehensive therapeutic effect on SCI mice, and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI. Moreover, the levels of Mac-1 and integrin α4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states. Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.