Macrophage membrane-modified reactive oxygen species-responsive prodrug self-assembled nanoparticles for the targeted treatment of traumatic spinal cord injury

•Overcoming the blood-spinal cord barrier to deliver prodrug.•In situ release of prodrug in response to reactive oxygen species.•Realizing multifunctional synergistic treatment of spinal cord injuries. Secondary injury has a tremendous impact on the recovery of motor function after traumatic spinal cord injury (SCI). The microenvironmental reactive oxygen species (ROS) and inflammatory bursts in the spinal cord tissues cause secondary injury that can further lead to neuronal apoptosis, which in turn exacerbates the loss of mobility and sensory function. Due to the presence of the blood–spinal cord barrier (BSCB), current clinical medicine is unable to effectively improve the microenvironment after SCI at a safe dose. In this experiment, macrophage membrane-modified ROS-responsive self-assembled methylprednisolone-S-docosahexaenoic acid prodrug nanoparticles (MΦ@MP-S-DHA) were designed to achieve targeted therapy across the BSCB. The monosulfide bond (-S-) responds to ROS in situ and attenuates ROS levels while releasing methylprednisolone (MP) and docosahexaenoic acid (DHA), which exert anti-inflammatory and neuroprotective effects. In vitro experiments have shown that MΦ@MP-S-DHA is released more rapidly by ROS. Cellular and mouse experiments further illustrated that MΦ@MP-S-DHA reduced ROS, malondialdehyde (MDA) and superoxide anion levels and maintained superoxide dismutase (SOD) activity after SCI. Moreover, MΦ@MP-S-DHA reduced the expression of inflammatory factors (TNF-α, IL-1β and IL-6) and the levels of apoptotic factors (caspase-3 and cleaved caspase-3) after SCI. On the 28th day, the SCI mice treated with MΦ@MP-S-DHA achieved a BMS score of 6 and better recovery of hindlimb movement. Therefore, MΦ@MP-S-DHA provides a potential therapeutic strategy to effectively exert multifaceted improvements in the microenvironment after SCI.