Microenvironment Self‐Adaptive Nanomedicine Promotes Spinal Cord Repair by Suppressing Inflammation Cascade and Neural Apoptosis

Abstract Despite various biomaterial‐based strategies are tried in spinal cord injury (SCI), developing safe and effective microinvasive pharmacotherapy strategies is still an unmet clinical need. Stimuli‐responsive nanomedicine has emerged as a promising non‐invasion technology, which enhances drug delivery and promotes functional recovery following SCI. Considering the multiple progressive pathological events and the blood spinal cord barrier (BSCB) associating SCI, a microenvironment self‐adaptive nanoparticle (custom‐designed with rabies virus glycoprotein 29‐RVG29 and hyaluronic acid‐HA, RHNP) capable of consistently crossing the BSCB and selectively targeting inflammatory cells and neural cells based on different stages of SCI are developed. The data indicated that RHNP can effectively traverse the BSCB through RVG29, and adaptively modulate cellular internalization by selectively exposing either HA or RVG29 through diselenide bonds, depending on pathological reactive oxygen species (ROS) signals. Furthermore, curcumin is loaded into RHNP (RHNP‐Cur) to improve motor function and coordination of hind‐limbs in a traumatic SCI mouse model. This study finds that RHNP‐Cur exhibited inhibitory effects on the inflammatory cascade originating from M1 microglia/macrophages and neurotoxic astrocytes, and protected neural cells from inflammation‐induced apoptosis during nerve regeneration. Collectively, the work provides a microenvironment self‐adaptive nanomedicine which enables efficient microinvasive treatment of SCI.