Nose-to-brain delivery of multimodal nanoregulator restores metal-redox homeostasis and protects mitochondrial integrity for triple inhibitions of neuronal death in radiation-induced brain injury.

Abstract

Radiation-induced brain injury (RIBI) has emerged as a severe complication of cranial radiotherapy, substantially impairing patients' quality of life. Current therapies mainly rely on anti-apoptotic drugs with limited efficacy. Despite advances in understanding neuronal death in RIBI, efficient neuroprotective strategies are still lacking. Herein, we identify that beyond apoptosis, neuronal ferroptosis and cuproptosis are key drivers of RIBI. To simultaneously inhibit all three death pathways, unlike traditional approach based on small-molecular inhibitors and their combinations, we propose an innovative strategy to disrupt the vicious cycle of ROS/Fe3+/Cu2+ overload and mitochondrial dysfunction that co-drive the three cell death modalities. And a therapeutic nanodot (SPDA-SeMet) is facilely engineered by conjugating natural selenomethionine onto small-sized polydopamine nanoparticles. In RIBI mice, therapeutic outcome of SPDA-SeMet significantly outperforms neuroprotective comparator Edaravone/Dexborneol. Mechanistically, negatively-charged surface and ultrasmall size enable rapid mucus penetration and enhanced nose-to-brain delivery, and then SPDA and SeMet modules work together to restore ROS/Fe3+/Cu2+ homeostasis and preserve mitochondrial integrity in neurons via enhanced capacity in Fe3+/Cu2+ chelation, ROS scavenging, mitochondrial colocalization, thereby efficiently inhibiting neuronal apoptosis/ferroptosis/cuproptosis and inflammation. Our findings establish an essential role of neuronal ferroptosis/cuproptosis/apoptosis in RIBI pathogenesis, and provides a therapeutic nanoplatform regulating complex pathological processes for targeted therapy.

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