Abstract

Facial nerve injury (FNI) is a common form of peripheral nerve damage that often results in incomplete functional recovery due to a hostile microenvironment characterized by excessive oxidative stress and inflammatory activation. These pathological conditions disrupt Schwann cell homeostasis, impair myelin maintenance, and hinder nerve regeneration. Although ferroptosis, an iron-dependent lipid peroxidation-driven form of regulated cell death, has been implicated in peripheral nerve disorders, its involvement in acute FNI remains not fully defined. In this study, transcriptomic analysis of injured facial nerve tissue suggested ferroptosis-related transcriptional alterations and lipid peroxidation-associated cellular injury during the acute phase of FNI, including changes in ferroptosis-related gene expression, decreased GPX4 levels, and increased 4-HNE accumulation. To modulate this complex microenvironment, we developed a peripheral nerve-targeted, ROS-responsive liposomal nanoplatform (F-MHC@PNRLs) co-delivering Ferrostatin-1 (Fer-1) and Mn-doped CeO 2 nanozymes (MHC). The designed system integrates complementary mechanisms, where MHC provides catalytic ROS-scavenging activity to regulate upstream oxidative stress, while Fer-1 acts downstream to suppress lipid peroxidation propagation. In addition, NP41 peptide modification enhances peripheral nerve-associated retention and lesion-site accumulation following local administration. In a mouse FNI model, F-MHC@PNRLs effectively reduced oxidative stress, modulated macrophage polarization toward a reparative phenotype, and was associated with activation of NRF2/HO-1 antioxidant signaling while inhibiting NF-κB/MAPK-mediated inflammatory responses. Furthermore, F-MHC@PNRLs alleviated Schwann cell injury, preserved mitochondrial homeostasis, and promoted remyelination, leading to improved functional and electrophysiological recovery. Importantly, the formulation exhibited favorable preliminary biosafety in vivo. Collec