Selective Membrane Protein Enrichment Enables Defined Biomimetic Nanoparticles for Endothelial Targeting

ABSTRACT Nanoparticles offer a promising strategy for targeted drug delivery while reducing off‐target toxicity. Biomimetic nanoparticles, which integrate native cell components, enhance biological compatibility but often suffer from poorly defined protein compositions that hinder reproducibility and clinical translation. Here, we present a next‐generation biomimetic approach to engineer Particular Nanoparticles (PNPs)‐ formulation enriched with specific, functionally relevant membrane proteins for precise control and tunability. We incorporated leukocyte adhesion proteins (including CD18, CD11a, and CD11b) into the nanoparticle membrane to enhance targeting of inflamed sites. Using a 2D microfluidic model that mimics human blood vessels, adhesion‐enriched PNPs demonstrated significantly improved endothelial interactions and greater accumulation under flow at inflamed endothelium compared to conventional Leukosomes. This protein‐defined biomimetic nanoparticle platform offers enhanced targeting efficiency, improved reproducibility, and translational potential for inflammation‐targeted therapies.