Biomimetic membrane-coating zinc sulfide nanoparticles for anti-inflammatory combined neuroprotective therapy for spinal cord injury

Spinal cord regeneration remains challenging due to complex inflammatory microenvironments, imbalances in metal ions, and obstacles to neuronal regeneration following spinal cord injury (SCI). Herein, microglial cell membranes coated with zinc sulfide nanoparticles modified with albumin (ZnS@BSA@MM) were designed as an anti-inflammatory combined neuroprotective therapy for SCI. ZnS@BSA@MM NPs were constructed via albumin modification and membrane extrusion and exhibited ROS-scavenging abilities comparable to those of natural products and slow H₂S release under acidic conditions. <i>In vitro</i> and <i>in vivo</i> experiments demonstrated the outstanding therapeutic effects of the ZnS@BSA@MM. In detail, the released H₂S and Zn²⁺ not only inhibit microglial activation through the NF-κB signaling axis but also promote the axonal growth of neurons under pathological conditions. Notably, microglial cell membranes effectively deliver ZnS@BSA to the lesion area. Finally, ZnS@BSA@MM facilitated the axonal regeneration of neurons in SCI, suppressed inflammatory responses, and activated multiple pathways, including cytokine-cytokine receptor interactions, neuroactive ligand-receptor interactions, and cAMP signaling. Collectively, this work highlights the anti-inflammatory and neuroprotective effects of ZnS@BSA@MM NPs, featuring satisfactory H₂S release and Zn²⁺ supplementation under membrane-targeting conditions for SCI therapy.