In situ transformable fibrillar networks ameliorate secondary brain injury after intracerebral hemorrhage by...

Intracerebral hemorrhage (ICH) is among the most severe stroke subtypes, especially the secondary brain injury synergistically driven by oxidative stress and neuroinflammation, which leads to severe progressive tissue damage and neurological deterioration. Currently, there are no effective and long-lasting targeted treatments for secondary brain injury caused by ICH. Here, we report an in situ biomimetic self-assembly strategy based on a fibrillar, transformable peptide (NKF) that coordinately suppresses oxidative stress and neuroinflammation. In aqueous solution, NKF self-assembles into nanoparticles; upon binding to KEAP1 in microglia, however, it undergoes an in situ transformation into nanofibrils, thereby enhancing intracellular retention and sustaining KEAP1 sequestration. In cellular and rat ICH models, NKF promotes sustained Nrf2 nuclear translocation and ARE-dependent transcription, resulting in enhanced antioxidant defense, attenuated pro-inflammatory signaling, and a shift in microglial phenotype towards a neuroprotective anti-inflammatory state. This physical conformation transformation strategy based on lesion-responsive peptide biomimetic assembly establishes a generalizable nanoplatform for durable activation of an endogenous neuroprotective pathway.