Biomimetic Cell-Membrane-Guided Precision Delivery of Gold Nanoclusters for Targeted Alleviation in Acute Lung Injury

Acute lung injury (ALI) and its severe sequela, acute respiratory distress syndrome (ARDS), remain life-threatening conditions with high morbidity and mortality. However, effective targeted therapeutics for ALI are still lacking. Biocompatible gold nanoclusters (AuNCs) with intrinsic immunomodulatory activity have shown a promising application in ALI alleviation, but their clinical potential is constrained by insufficient accumulation at pulmonary lesion sites following systemic administration. To overcome this critical barrier, we developed two biomimetic delivery platforms by encapsulating TAT peptide-protected gold nanoclusters (TAT-AuNCs; designated as TA) with natural cell membranes that derived from either lung bronchial epithelial cells (TA@CMVs-MLE) or M1-polarized macrophage (TA@CMVs-M1M), respectively. Both nanoplatforms displayed excellent biosafety profiles and achieved substantially enhanced pulmonary accumulation and better therapeutic outcomes than free TA in lipopolysaccharide (LPS)-induced ALI mice, after intravenous administration. Nevertheless, TA@CMVs-M1M achieved markedly superior therapeutic outcomes than TA@CMVs-MLE, although their efficiency in delivering TA to the lungs was comparable. Mechanistic studies indicated that TA@CMVs-M1M can be selectively taken up by inflammatory macrophages and has an ability to neutralize proinflammatory cytokines, which is not possessed by TA@CMVs-MLE. Therefore, TA@CMVs-M1M exhibited a superior attenuation on inflammatory lung injury. These results demonstrated that the M1 macrophage membrane not only enables AuNCs to achieve precise targeting of pneumonia lesions but also possesses inherent inflammatory cytokine neutralization capabilities, which can synergize with the transcriptional inhibitory activity of AuNCs on inflammatory cytokines to enhance the targeted alleviating of ALI. Thus, this work establishes a translatable nanotheranostic strategy that merges natural immune-cell tropism with intrinsic AuNCs pharmacology for next-generation ALI management.