Super homotypic targeting by surface engineering of extracellular vesicles

Homotypic targeting is the inherent ability of cells to preferentially interact with cells of the same type, a phenomenon seen in cell adhesion, tissue formation and immune responses. However, its potential remains underexploited. Here we report a strategy to substantially enhance homotypic targeting through extracellular vesicles secreted by cells. By engineering the surface of small extracellular vesicles (sEVs) with lanthanides, we amplify specific cell–sEV interactions by more than 25-fold, enabling the selective capture of sEVs by cells of the same lineage even in the presence of excess off-target sEVs. We term this effect ‘super homotypic targeting’. Super homotypic targeting provides a means to distinguish sEVs of different origins within highly heterogeneous sEV populations and enables two applications: using cells to detect specific sEVs and using sEVs to detect specific cells, specifically demonstrated here in the context of cancer detection from blood samples. Super homotypic targeting could hold potential for diagnostics, immunotherapy, drug delivery, rejuvenation and tissue engineering.