Apoptotic-body-inspired nanoplatform targeting the lung-macrophage-mitochondrial axis for acute lung injury therapy.

Acute lung injury (ALI), a life-threatening inflammatory syndrome driven by macrophage polarization imbalance, triggers uncontrolled cytokine storms and alveolar-capillary barrier collapse. While macrophage-targeted immunomodulation holds therapeutic promise, current strategies suffer from imprecise cellular targeting and inadequate functional reprogramming. To address this, we developed an inhaled biomimetic apoptotic body-mimicking nanoplatform (CeCPT@PSL). Its phosphatidylserine-containing liposomal (PSL) shell replicates the "eat-me" signaling of apoptotic bodies to enable macrophage targeting and immunomodulation. Inspired by the organelle-regulating capacity of apoptotic cargo, the encapsulated synthetic mitochondrial-targeting nanozyme complexes (CeCPT) execute precision mitochondrial restitution through redox homeostasis restoration. This dual-pathway strategy achieves synergistic therapy by concurrently modulating macrophage function and repairing damaged mitochondria, thereby enhancing macrophage repolarization. In murine ALI models, inhaled CeCPT@PSL concurrently attenuated inflammatory cascades and resolved mitochondrial impairment via targeting lung-macrophage-mitochondrial axis, and restored pulmonary function. This bio-inspired multi-function platform establishes a heuristic strategy wherein artificial nanovesicles recapitulate cellular functions to resolve dysregulated pathological cascades, offering a promising therapeutic avenue for intractable inflammatory diseases.