Engineered exosome MDC@Ex-γ3-CeO₂@PDA for multi-target therapy of sepsis-induced acute lung injury

Sepsis-induced acute lung injury (ALI), with a complex pathogenesis, currently lacks clinically effective multi-target therapeutic strategies. Musca domestica cecropin (MDC), a promising antimicrobial, anti-inflammatory, and endothelial-repairing peptide, is limited by its high molecular weight and poor selectivity. Here, we developed an engineered exosome-based drug delivery system, MDC@Ex-γ3-CeO₂@PDA, for targeted treatment of sepsis-induced ALI. This system encapsulates MDC within exosomes derived from human adipose-derived mesenchymal stem cells (hAD-MSCs), with surface modification by CeO₂@PDA nanozymes and PEG-γ3 targeting peptides for lung targeting. In a septic male mouse model, the intravenous administration of these engineered exosomes resulted in targeted accumulation in injured lung tissues, significantly alleviating cytokine storms, oxidative stress, endothelial barrier damage, and lung pyroptosis. Additionally, the therapy modulated immune cell distribution by increasing CD4⁺and CD8⁺ T cell proportions while reducing neutrophils and regulatory T cells (Tregs), effectively mitigating immunosuppression and improving survival. Notably, it also restored gut microbiota homeostasis. The study provides a delivery strategy for MDC clinical translation and opens avenues for treating sepsis and associated organ injuries. We engineered MDC-loaded exosomes modified with γ3 peptide and CeO₂@PDA to target inflamed lung tissue in septic mice. The engineered exosomes significantly attenuated lung injury, reduced systemic inflammation, and improved survival in both LPS- and CLP-induced sepsis models.