Development of Ti3CN nanosheets (NSs) for radiation pneumonitis therapy: ROS scavenging and ferroptosis inhibition

• This study develops few-layer Ti 3 CN nanosheets with strong intrinsic antioxidative capacity, enabling rapid removal of reactive oxygen species and effective inhibition of lipid peroxidation. • The nanosheets prevent macrophage ferroptosis and restore immune balance by regulating macrophage polarization under radiation-induced oxidative stress. • In vivo experiments demonstrate that these nanosheets markedly alleviate radiation-induced lung injury, providing a promising nanomaterial-based protective strategy for radiation pneumonitis. Radiation pneumonitis (RP), a major dose-limiting toxicity of thoracic radiotherapy, is primarily driven by excessive reactive oxygen species (ROS) accumulation and proinflammatory macrophage activation, yet effective therapeutic strategies remain unavailable. Herein, we constructed Ti 3 CN nanosheets (Ti 3 CN NSs) via HF etching followed by ultrasonic exfoliation, enabling potent catalytic ROS scavenging and immunomodulatory activities. Leveraging their intrinsic antioxidative properties, Ti 3 CN NSs were systematically evaluated across cell, mice, and lung organoid models, demonstrating robust elimination of radiation-induced ROS and restoration of pulmonary redox homeostasis. Transcriptome sequencing combined with pathway enrichment analysis revealed that Ti 3 CN NSs alleviated radiation-induced macrophage ferroptosis, thereby rebalancing macrophage polarization by suppressing M1 and promoting M2 polarization. In vivo , Ti 3 CN NSs attenuated RP progression and facilitated structural repair of injured lung tissue. Collectively, this work proposes a nanomaterial-based strategy for the prevention and treatment of RP, and highlights the critical roles of macrophage polarization and ferroptosis in radiation-induced pulmonary inflammation.