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Although intracranial radiotherapy is commonly used to treat both intracranial and extracranial tumors, it inevitably causes radiation-induced brain injury (RBI). This can trigger serious clinical events, such as progressive cognitive impairment and irreversible neurological damage. However, the lack of effective clinical drug treatments highlights the urgent need for new therapeutic targets and the development of effective drug delivery platforms.Therefore, in this study, we identified through spatial transcriptomics that neuronal cuproptosis plays a crucial role in RBI. In addition, we constructed a biomimetic delivery system using mesoporous silica nanoparticles to co-load UK5099 (a cuproptosis inhibitor) and melatonin (a neuroinflammation inhibitor), which was then cloaked with macrophage membranes for targeted delivery. Through nose-to-brain delivery, we found that this system rapidly distributes in the injured brain to release UK5099 and inhibit neuronal cuproptosis.At the same time, the release of melatonin alleviates neuroinflammation by eliminating reactive oxygen species, inhibiting overactivation of glial cells, and downregulating pro-inflammatory cytokines. Therefore, this system significantly improves behavioral function in RBI mice, reduces brain edema, and increases neuron survival, surpassing single treatments based on tooth extraction disorders or neuroinflammation alone. In addition, it preliminarily reveals the potential therapeutic mechanisms. These results not only highlight the importance of neuronal copper dysregulation in RBI but also suggest that it is a promising approach for RBI treatment.
References:
DOI: 10.1016/j.biomaterials.2025.123809
