Engineered extracellular vesicles loaded in boronated cyclodextrin framework for pulmonary delivery.

Extracellular vesicles (EVs) are promising therapeutic carriers for their ideal nano-size and intrinsic biocompatibility, while rapid clearance and limited targeting ability are the major setbacks of EVs. With minimal absorption into the systemic circulation, inhalation for pulmonary disease therapy minimizes off-target toxicity to other organs and offers a safe and effective treatment for respiratory disorders. Herein, a nano-grid carrier made of boronated cyclodextrin framework (BCF) was prepared for pH/HO responsive release of EVs. A novel design of cyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide (RGD)-modified milk-derived EVs (mEVs) loaded in the BCF particles (RGD-mEVs@BCF) was developed for pulmonary delivery. The results indicated that RGD-mEVs showed superior anti-inflammatory activity in contrast with mEVs in vitro. BCF was able to capture and protect RGD-mEVs, which showed extended-release profiles and responsiveness. Pulmonary administration of RGD-mEVs@BCF showed favorable biocompatibility in rats. Taken together, RGD-mEVs@BCF features biocompatibility and pH-responsive mEVs release as a therapeutic platform for pulmonary delivery of drugs to treat lung diseases, especially for inflammatory diseases.