Inhalable biomimetic apoptotic bodies enable targeted LXRα agonist delivery to lung macrophages for acute lung injury therapy.

Acute lung injury (ALI) is a common critical illness driven by uncontrolled pulmonary inflammation, with hyperactivated macrophages sustaining pro-inflammatory cytokine release. Activation of liver X receptor α (LXRα) can suppress inflammatory gene expression. However, clinical translation of LXRα agonists such as T0901317 (T09) is limited by off-target effects, particularly hepatotoxicity. Here, we developed a biomimetic controlled-release platform (AB/NPs@T09) using mesenchymal stem cell (MSC)-derived apoptotic bodies (ABs) as natural carriers for T09. The structural properties of ABs facilitated macrophage uptake via the efferocytosis pathway. Inhalation administration of AB/NPs@T09 enabled dual organ-cell targeting, increasing pulmonary drug accumulation while markedly reducing liver distribution. In an ALI mouse model, inhaled AB/NPs@T09 at a low dose (1 mg/kg) achieved anti-inflammatory efficacy comparable to that of high-dose intraperitoneal injection (10 mg/kg), without inducing hepatotoxicity. The biomimetic platform presented here not only offers a new avenue for therapeutic intervention in clinical ALI, but also establishes a generalizable strategy for repurposing potent yet toxic small molecules in inflammatory diseases.