Engineered Young Brown Adipose Tissue-Derived Exosomes Alleviate Radiation-Induced Lung Injury by Promoting G Protein-Coupled Receptor 183 Ubiquitination

Acute radiation-induced lung injury is a serious and potentially life-threatening complication of radiotherapy for thoracic malignancies or accidental radiation exposure, characterized by high incidence, limited treatment options, and substantial mortality. To address the lack of effective therapies for preventing and treating radiation-induced lung injury, we developed an engineered nanoplatform, BAT-exo@Au, generated by functionalizing exosomes derived from young brown adipose tissue (BAT) with 1,2-distearoyl- sn -glycero-3-phosphoethanolamine–polyethylene glycol–thiol (DSPE-PEG-SH) and gold nanoparticles via chloroauric acid (HAuCl 4 ) incubation. Our results show that BAT-exo@Au was efficiently internalized by irradiated lung tissue and exerted radioprotective effects by suppressing reactive oxygen species production and attenuating radiation-induced inflammatory responses. In addition, BAT-exo@Au mitigated radiation-induced epithelial–mesenchymal transition while enhancing tumor radiosensitivity, suggesting a dual therapeutic advantage. Mechanistically, BAT-exo@Au reduced apoptosis and preserved mitochondrial membrane potential after radiation in vitro. Transcriptomic analysis identified G protein-coupled receptor 183 ( Gpr183 ) as a potential downstream target, showing upregulation after radiation but downregulation following BAT-exo@Au treatment. Further in vitro experiments demonstrated that BAT-exo@Au promoted the interaction between Gpr183 and the E3 ubiquitin ligase NEDD4, facilitating Gpr183 ubiquitination and proteasomal degradation. This study suggests that exosomes derived from young BAT may serve as a therapeutic strategy for the prevention of radiation-induced lung injury. In conclusion, BAT-exo@Au shows promise as a preventive approach for radiation-induced lung injury, potentially through modulation of Gpr183 via enhanced Gpr183–NEDD4 interaction and ubiquitination.