<p>NAD⁺ is a critical cofactor for oxidative phosphorylation, key enzymes in glycolysis and the tricarboxylic acid cycle. It has been reported that supplementation with exogenous NAD⁺ precursors can reverse NAD⁺ depletion and improve mitochondrial function. However, the clinical application of exogenous NAD⁺ is limited by its insufficient targeting, short half-life, and instability, which restricts its further use in acute lung injury (ALI). Here, we designed a cascade-targeted biomimetic nanoparticle with cascade targeting and pH responsiveness, capable of delivering NAD⁺ specifically to the mitochondria of lung epithelial cells to scavenge reactive oxygen species. In vivo experiments demonstrate that these nanoparticles can remain enriched in lung tissue over an extended period and inhibit ferroptosis by activating AMPK, restoring mitochondrial homeostasis and the immune microenvironment balance. Additionally, the nanoparticles promote macrophage M2 polarization and CCL18 secretion, supporting the integrity of the lung epithelium. In conclusion, our cascade-targeted mitochondrial biomimetic nanoparticles offer a novel approach for the treatment of ALI.</p> Graphical Abstract <p></p>