Liposomes and nanoparticles that bind selectively to cell-surface receptors can target specific populations of cells. However, chemical conjugation of ligands to these particles is difficult to control, frequently limiting ligand uniformity and complexity. In contrast, the surfaces of living cells are decorated with highly uniform populations of sophisticated transmembrane proteins. Toward harnessing cellular capabilities, here we demonstrate that plasma membrane vesicles (PMVs) derived from donor cells can display engineered transmembrane protein ligands that precisely target cells on the basis of receptor expression. These multi-functional targeting proteins incorporate (i) a protein ligand, (ii) an intrinsically disordered protein spacer to make the ligand sterically accessible, and (iii) a fluorescent protein domain that enables quantification of the ligand density on the PMV surface. PMVs that displayed targeting proteins with affinity for the epidermal growth factor receptor (EGFR) bound at increasing concentrations to breast cancer cells that expressed increasing levels of EGFR. Further, as an example of the generality of this approach, PMVs expressing a single domain antibody against GFP bound to cells expressing GFP-tagged receptors with a selectivity of approximately 50:1. Our results demonstrate the versatility of PMVs as cell targeting systems, suggesting diverse applications from drug delivery to tissue engineering.

Cell‐derived plasma membrane vesicles extracted from genetically engineered donor cells can selectively target cells based on their receptor expression profiles, as demonstrated by J. C. Stachowiak and co‐workers on page 3837. These engineered donor cells have a stable expression of transmembrane protein ligands that contain multiple domains, including a targeting ligand, a spacer and a fluorophore.