ROS ‐Responsive Quercetin Nanoparticles Improve the Prognosis of Traumatic Brain Injury by Inhibiting Aberrant Nrf2‐Keap1 Signaling Pathway Activation

ABSTRACT Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide, with secondary injury recognized as a critical therapeutic target. Quercetin (QR), a natural flavonoid, exerts antioxidant and anti‐inflammatory effects by modulating the Nrf2–Keap1 pathway and shows neuroprotective potential in various neurological disorders. In this study, network pharmacology analysis identified 496 overlapping targets of QR and TBI, further highlighting the pivotal role of the Nrf2–Keap1 pathway in TBI treatment. However, the poor blood–brain barrier (BBB) permeability and low bioavailability of QR hinder effective brain‐targeted delivery and limit its clinical translation. To address these challenges, we developed CAQK peptide‐modified, reactive oxygen species (ROS)‐responsive nanoparticles (C‐PPS/Q), using PPS 120 as the core for targeted QR delivery. C‐PPS/Q exhibited ROS‐triggered QR release, significantly enhanced HT22 cell uptake in vitro, reduced ROS levels and apoptosis. In a TBI mouse model, C‐PPS/Q specifically accumulated at the lesion site, prolonged the half‐life of QR, demonstrated excellent biocompatibility, preserved BBB integrity, attenuated neuroinflammation, inhibited aberrant Nrf2‐Keap1 pathway activation, and markedly improved neurological function. Collectively, C‐PPS/Q nanoparticles effectively mitigate secondary brain injury after TBI and represent a promising brain‐targeted therapeutic strategy for TBI management.