Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Post-traumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may beneficially effects for the treatment of secondary brain damage after TBI. Herein, a cysteine-alanine-glutamine-lysine (CAQK) peptide-modified ß-lactoglobulin (ß-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-ß-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-ß-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-ß-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a new approach for reducing the secondary spread of TBI. Overall design: The brain tissues were collected from the brain injury (or the same anatomical site) in the Sham group (only the skull was drilled open, the dura was opened, and no brain tissue was damaged), the TBI group (the brain injury model of heavy fall), and the C-ß-LG/DSF group (the tail vein injection of C-ß-LG/DSF after TBI), and the brain tissues were collected for high-throughput RNA-seq. The expression of pyroptosis and inflammation-related genes in each group was analyzed.