Small extracellular vesicles (sEVs) are natural "nano-couriers" in the human body. They are known for the low immunogenicity and high biocompatibility which make them ideal carriers for drug delivery and disease diagnosis. However, their clinical translation is limited by donor cell source dependency and inadequate targeting capabilities.

In a study published in Journal of Extracellular Vesicles, a research team led by Prof. YANG Hui from the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences developed a universal micro-nanofluidic platform called the EV Surface-Engineering Device (ExoSE) which enables efficient and standardized surface engineering of sEVs, significantly improving their targeting capabilities.

ExoSE consists of two interconnected modules: "Loading" and "Mixing." The loading module utilizes a nanofluidic structure to achieve mechanoporation of sEVs, allowing insertion of lipids. And the mixing module uses a microfluidic structure to promote conjugation of ligand molecules.

This approach eliminates the dependence on donor cells, which is applicable to diverse cell sources and high-yield sources such as milk-derived sEVs, and is compatible with various ligands including peptides, aptamers and proteins. Experimental data showed that ExoSE achieved >97% lipid incorporation efficiency, outperforming co-incubation techniques. NanoFCM analysis revealed a 3- to 6-fold increase in ligand binding per sEV.

Besides, engineered sEVs demonstrated excellent targeting performance in both in vitro and in vivo models. RGE-peptide-modified sEVs showed an over 3-fold increase in blood-brain barrier penetration and significantly deeper glioma spheroid infiltration. AS1411 aptamer-conjugated sEVs showed a 77.8% targeting specificity toward breast cancer cells. Animal studies confirmed the accumulation of engineered sEVs in the brain with on observed liver or kidney toxicity.

This device represents a transformative advancement in sEV engineering, establishing a standardized and scalable framework for precision-targeted sEV therapeutics with enhanced clinical potential.