Combined Regulation of Macrophage Phagocytosis by the Size, Shape, and Mechanical Stiffness of Concave Core–Shell Artificial Oxygen Carriers

Red blood cell-mimetic artificial oxygen carriers (AOCs) with concave morphology were developed as core-shell microparticles consisting of perfluorooctyl bromide and a polydimethylsiloxane-based thermoplastic elastomer (PFOB/PDMS-TPE). Their size, shape, and mechanical stiffness were tunable via a high-shear homogenization method, yielding diameters ranging from 2 μm (comparable to human platelets) to 8 μm (comparable to human red blood cells). These AOCs exhibited both oxygen-carrying capability and excellent in vitro biocompatibility. Compression testing demonstrated that apparent particle stiffness could be modulated by adjusting the core-to-shell (C/S) ratio without altering the material composition. Phagocytosis assays using RAW 264.7 macrophages showed that 2 μm-diameter spherical particles were readily internalized, whereas concave 2 μm-diameter AOCs exhibited markedly reduced uptake. In contrast, both 8 μm spherical particles and concave AOCs exhibited limited phagocytosis. Furthermore, competitive phagocytosis assays, in which macrophages were simultaneously exposed to two distinct AOC types, revealed a combined interplay among size, shape, and mechanical stiffness. Notably, 2 μm concave AOCs were phagocytosed less efficiently than 4 μm spherical counterparts, and concave AOCs, regardless of size, consistently evaded macrophage uptake under mixed-particle conditions. These findings provide key design principles for engineering deformable, shape-optimized microparticles, such as AOCs and drug-delivery carriers, that effectively evade macrophage phagocytosis.