Bio-orthogonal-labeled exosomes reveals specific distribution in vivo and provides potential application in ARDS therapy.

Exosomes derived from specific cells may be useful for targeted drug delivery, but tracking them in vivo is essential for their clinical application. However, their small size and complex structure challenge the development of exosome-tracking techniques, and traditional labeling methods are limited by weak affinity and potential toxicity. To address these issues, here we developed a novel bio-orthogonal labeling strategy based on phosphatidylinositol derivatives to fluorescently label exosomes from various human and mouse cell types. The different cell-derived exosomes revealed organ-specific distribution patterns and a favorable safety profile. Notably, 4T1 cell-derived exosomes specifically targeted the lungs. When used as drug carriers loaded with anti-inflammatory resveratrol, these exosomes showed significant therapeutic efficacy in mice with acute respiratory distress syndrome (ARDS), effectively reducing inflammatory responses, mitigating pulmonary fibrosis, and restoring lung tissue morphology and function. Our findings provide a novel exosome labeling strategy and an invaluable tool for their in vivo tracking and targeting screening, while exosomes that specifically target the lungs offer a potential therapeutic strategy for organ-specific diseases such as ARDS.