Helper lipid-engineered extracellular vesicles enable PET imaging-guided pulmonary siRNA delivery to treat lung metastasis.

Pulmonary diseases, including malignancies and chronic airway diseases, pose substantial global health challenges requiring advanced therapies. While extracellular vesicles (EVs) show promise as natural delivery vectors, their clinical application is limited by hepatic tropism. To date, no rational design for selectively lung-targeted EVs has been developed. Here, we modulate tumor cell-derived medium vesicles (TMVs) with cationic DOTAP lipids to alter their internal charges and tissue tropism. We accurately tracked the biodistribution of TMVs-DOTAP in vivo via highly sensitive positron emission tomography (PET) imaging, which clearly indicates their enhanced lung-targeting specificity. Furthermore, we engineered an EV-based siRNA delivery system (TMVs-DOTAP/siPD-L1), which effectively targets and silences PD-L1 in melanoma lung metastasis, leading to enhanced tumor immune responses. Mechanistic studies revealed the role of the protein corona in determining lung/liver tropism. This study provides a promising strategy for nucleic acid delivery and immunotherapy in pulmonary diseases.