Cel-LDH dual-functional nanotherapy simultaneously promotes microglial efferocytosis and alleviates neuronal apoptosis for spinal cord injury recovery

Traumatic spinal cord injury (SCI) can cause severe central nervous system damage. Efferocytosis, an intrinsic regulatory mechanism through which microglia eliminate apoptotic cells, is suppressed because of the local ischaemic and hypoxic microenvironment after spinal cord injury (SCI). In addition, hypoxia and reoxygenation (H/R) trigger mitochondrial respiratory chain electron leakage, leading to the massive generation of mitochondrial reactive oxygen species (mtROS), impairing the energy supply and causing oxidative stress damage in neurons, which induces neuronal apoptosis. Synergistic therapies targeting efferocytosis and neuronal apoptosis are important for recovery after SCI. In this study, by loading celastrol in a layered double hydroxide, a multifunctional nanoparticle, Cel-LDH, was developed to facilitate SCI recovery by concurrently normalizing efferocytosis homeostasis and inhibiting neuronal apoptosis. Cel-LDH composite nanoparticles strongly scavenged ROS and preserved mitochondrial homeostasis, thus regulating apoptosis-related proteins, including Bax and Bcl-2, and effectively inhibiting the apoptotic process of neurons. Furthermore, Cel-LDH nanoparticles promoted autophagy, inhibited the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (Sting) pathway to modulate the anti-inflammatory phenotypic transformation of microglia, and subsequently restored the efferocytosis homeostasis of microglia, thus suppressing inflammatory cascades and creating favourable microenvironments for the repair of SCI. This approach not only remodels the dysfunctional efferocytosis capacity but also inhibits neuronal apoptosis, providing a new therapeutic strategy for SCI.