Spatiotemporal Delivery of a Cell-Free DNA Scavenger for Detoxification and Neural Repair after Spinal Cord Injury

Spinal cord injury (SCI) poses a significant therapeutic challenge, largely due to the formation of an inhibitory microenvironment. In this study, cell-free DNA (cfDNA) was found to induce neuroinflammation and accelerate neuronal apoptosis. Leveraging the neuroprotective properties of extracellular vesicles from induced pluripotent stem cell-derived neural stem cells (Nev), a spatiotemporally controlled cfDNA scavenger (Nev-RA) was established by functionalizing the Nev with oligoarginines and reactive oxygen species (ROS)-cleavable poly(ethylene glycol)-angiopeps. Following angiopep-mediated penetration of the blood-spinal cord barrier and ROS-sensitive cleavage at the lesion site, the exposed oligoarginines scavenge pathogenic cfDNA, thereby attenuating toll-like receptor 9-mediated inflammation, while the Nev facilitates the survival of impaired neurons. This biomimetic strategy concurrently addresses the dual barriers of a hostile inflammatory microenvironment and an insufficient intrinsic repair capacity. Collectively, this work reveals an important therapeutic target for SCI and proposes a promising and translatable treatment paradigm.