Extracellular vesicles (EVs) are promising therapeutic carriers due to their optimal nano-size and intrinsic biocompatibility. However, there are disadvantages such as rapid clearance and limited targeting ability. For respiratory diseases, inhalation administration can minimize off-target toxicity. Exploring safe and effective drug delivery systems based on EVs is essential for varied respiratory diseases.

In a study published in Carbohydrate Polymers, a research team led by ZHANG Jiwen from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences synthesized a nano-grid structured carrier based on a boronated cyclodextrin framework (BCF), and revealed that BCF can capture and protect RGD-modified milk-derived EVs (RGD-mEVs@BCF).

Researchers constructed the nano-grid BCF with pH/H₂O₂ responsiveness by crosslinking cyclodextrin metal-organic frameworks (CD-MOFs) using a symmetric boronated compound. The nanowires had diameters ranging from 20 to 100 nm and the size of voids formed within the nano-grid was from 10 to 300 nm. EVs, measuring 50 to 150 nm, are membrane-derived nanovesicles released by cells into extracellular space, aligning with the size of the voids in BCF. 

Then, researchers made a novel design of cyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide (RGD)-modified mEVs encapsulated within BCF particles (RGD-mEVs@BCF) for pulmonary delivery. RGD was used to modify mEVs to enhance target and anti-inflammatory abilities. RGD-mEVs showed superior anti-inflammatory activity in contrast with mEVs in vitro, whilst the BCF was used to capture and protect RGD-mEVs. Pulmonary administration of RGD-mEVs@BCF demonstrated favorable biosafety. 

Given that BCF was synthesized from cyclodextrins, it was an ideal delivery carrier for small molecule drugs. In addition, the amphipathic nature of EVs’ membrane provided a versatile platform for transporting both hydrophobic and hydrophilic molecules. Therefore, EVs@BCF emerges as a highly desirable drug carrier. As a therapeutic platform for pulmonary administration, RGD-mEVs@BCF features dual-responsive release behaviors and biosafety to treat lung diseases, especially inflammation.