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Seven polycaprolactones (PCL) with constant hydrophobicity but a varying degree of crystallinity prepared from the constitutional isomers ε-caprolactone (εCL) and δ-caprolactone (δCL) were utilized to formulate nanoparticles (NPs). The aim was to investigate the effect of the crystallinity of the bulk polymers on the enzymatic degradation of the particles. Furthermore, their efficiency to encapsulate the hydrophobic anti-inflammatory drug BRP-187 and the final in vitro performance of the resulting NPs were evaluated. Initially, high-throughput nanoprecipitation was employed for the εCL and δCL homopolymers to screen and establish important formulation parameters (organic solvent, polymer and surfactant concentration). Next, BRP-187-loaded PCL nanoparticles were prepared by batch nanoprecipitation and characterized using dynamic light scattering, scanning electron microscopy and UV-Vis spectroscopy to determine and to compare particle size, polydispersity, zeta potential, drug loading as well as the apparent enzymatic degradation as a function of the copolymer composition. Ultimately, NPs were examined for their potency in vitro in human polymorphonuclear leukocytes to inhibit the BRP-187 target 5-lipoxygenase-activating protein (FLAP). It was evident by Tukey’s multi-comparison test that the degree of crystallinity of copolymers directly influenced their apparent enzymatic degradation and consequently their efficiency to inhibit the drug target.