Light‐Responsive Oxygen Generation from Chlorella Hydrogels for Facial Nerve Injury Recovery: Crosstalk between M1/M2 Macrophages and Schwann Cells

Abstract Facial nerve injury (FNI), hindered by hypoxic microenvironments limiting Schwann cell (SCs) repair potential, remains a therapeutic challenge. We developed light‐responsive Chlorella hydrogels (C‐Gel) to modulate oxygen release and inflammation. In vitro, light‐activated C‐Gel enhanced RSC96 SC proliferation, migration, and secretion while reducing reactive oxygen species (ROS), hypoxia‐inducible factor‐1α (HIF‐1α), tumor necrosis factor‐alpha (TNF‐α), and interleukin‐6 (IL‐6). It also shifted macrophage polarization from pro‐inflammatory M1 (inducible nitric oxide synthase (iNOS) + /TNF‐α + ) to anti‐inflammatory M2 (arginase‐1 (Arg‐1) + /IL‐10 + ), with M2‐conditioned mediumboosting SCs production of neurotrophic factors (nerve growth factor, NGF; glial cell line‐derived neurotrophic factor, GDNF), adhesion molecules (neural cell adhesion molecule‐1, NCAM‐1), regeneration‐associated proteins (c‐JUN), and myelin components (myelin basic protein, MBP; myelin‐associated glycoprotein, MAG). In vivo, C‐Gel‐light therapy improved behavioral recovery in FNI rats, suppressed inflammation (ROS/HIF‐1α/TNF‐α), and enhanced SC‐mediated remyelination (S100 calcium‐binding protein, S100; neurofilament 200, NF200). RNA sequencing identified upregulated phosphoinositide 3‐kinase‐protein kinase (PI3K‐Akt) and calcium ion (Ca² + ) signaling pathways. This oxygen‐regulating, immunomodulatory biomaterial offers a dual‐action strategy to advance FNI rehabilitation by synergistically optimizing the regenerative microenvironment.