Brain‐Targeted Multifunctional Liposomes Reprogram Microglia via Anti‐Inflammatory Signaling and Reactive Oxygen Species Scavenging to Treat Post‐Traumatic Neuroinflammation

Traumatic brain injuries (TBIs) are often accompanied by severe neuroinflammation that markedly elevates the risk of neurodegeneration and cognitive impairment. Current insights reveal that the excessive accumulation of inflammatory microglial cells drives TBI‐associated inflammatory responses. However, inhibiting neuroinflammation through reprograming microglial cells is challenging as the blood‐brain barrier (BBB) severely impedes delivery of anti‐inflammatory drugs. To address these challenges, a nanointegrative TBI treatment strategy is reported that can reprogram inflammatory microglial cells into a reparative phenotype for abolishing post‐TBI neurodegeneration. Herein, methylprednisolone and Tempol are loaded into transactivator of transcription (TAT) peptide‐modified PEGylated liposomes to afford a liposomal microglial reprogramming platform (LMRP). After intravenous administration, the liposomes efficiently cross the BBB and accumulate in TBI sites to release the therapeutic payload, which cooperatively activates multiple anti‐inflammatory signaling pathways and scavenged reactive oxygen species for repolarizing inflammatory microglial cells to reparative phenotypes in situ, leading to effective amelioration of the neurodegeneration symptoms. In vivo analysis shows that LMRP treatment robustly recovers the neurological functions of TBI rat models with no obvious side effects, offering an approach for TBI treatment with clinical promise.