This study investigates the anti-inflammatory effects of iron-capsaicin-based nanoparticles (Fe-CAP NPs) in treating sepsis-induced acute lung injury (ALI). Fe-CAP NPs were synthesized by combining capsaicin and iron, and their efficacy was evaluated in both in vitro and in vivo models. In vitro, Fe-CAP NPs significantly reduced the expression of pro-inflammatory cytokines (TNF-α and iNOS) and increased the expression of anti-inflammatory cytokine transforming growth factor-β (TGF-β) in RAW 264.7 macrophage cells. The anti-inflammatory effects were mediated through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. In vivo, Fe-CAP NPs reduced the expression of inflammatory cytokines in mouse lungs, improved histopathological changes, and alleviated pulmonary capillary leakage. Fe-CAP NPs also showed minimal toxicity to major organs, demonstrating their safety and efficacy in treating ALI. The study provides evidence that Fe-CAP NPs can alleviate inflammation by inhibiting pro-inflammatory factors and increasing anti-inflammatory factors, thereby protecting lung tissue from damage.This study investigates the anti-inflammatory effects of iron-capsaicin-based nanoparticles (Fe-CAP NPs) in treating sepsis-induced acute lung injury (ALI). Fe-CAP NPs were synthesized by combining capsaicin and iron, and their efficacy was evaluated in both in vitro and in vivo models. In vitro, Fe-CAP NPs significantly reduced the expression of pro-inflammatory cytokines (TNF-α and iNOS) and increased the expression of anti-inflammatory cytokine transforming growth factor-β (TGF-β) in RAW 264.7 macrophage cells. The anti-inflammatory effects were mediated through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. In vivo, Fe-CAP NPs reduced the expression of inflammatory cytokines in mouse lungs, improved histopathological changes, and alleviated pulmonary capillary leakage. Fe-CAP NPs also showed minimal toxicity to major organs, demonstrating their safety and efficacy in treating ALI. The study provides evidence that Fe-CAP NPs can alleviate inflammation by inhibiting pro-inflammatory factors and increasing anti-inflammatory factors, thereby protecting lung tissue from damage.