Engineering Morphological Anisotropy to Control the In Vivo Transport Dynamics, Clearance, and Biodistribution of...

Shape governs function across scales in nature, from streamlined bacteria to biconcave red blood cells that navigate capillary flow. Inspired by these bio-geometries, we explore how nanoscale anisotropy can be engineered to control the dynamic transport and biodistribution of synthetic nanocarriers in the body. We fabricate anisotropic silica nanocapsules with precisely tunable asymmetry to dissect shape effects on nano-bio interactions under physiological flow. Under shear flow in vitro, increasing anisotropy markedly reduced cellular uptake, whereas this effect was much less pronounced under static conditions, revealing strong flow-shape coupling. In vivo, highly anisotropic nanocapsules exhibit prolonged circulation, with a 2.8-fold longer half-life than spherical counterparts and significantly reduced sequestration by the liver, spleen, and circulating blood cells. Mechanistic analyses attributed these effects to decreased phagocytic internalization by Kupffer cells, splenic macrophages, and circulating monocytes. Computational fluid dynamics simulations corroborated this phenomenon, demonstrating that greater anisotropy shifts particle trajectories away from vessel walls toward the central flow stream, lowering the chances of cellular interception. Together, these results establish nanoscale anisotropy as a critical determinant of nanoparticle transport, immune recognition, and clearance under flow. Anisotropy engineering therefore provides a nature-inspired framework for designing long-circulating, immune-evasive nanocarriers with improved therapeutic performance.