Abstract

Understanding how nanoparticles are sequestered in vivo requires moving beyond traditional organ level biodistribution toward cell-type-resolved analysis within major clearance organs. Although the liver has long been recognized as the primary site of nanoparticle elimination, the contributions of splenic macrophages and circulating immune cells-and the heterogeneity of cellular processing within the liver itself-remain insufficiently defined. Here, we conduct a systematic sub-organ level investigation of the size-dependent sequestration mechanisms of silica nanocapsules. Nanocapsules with representative diameters were quantitatively tracked across blood, liver, and spleen, enabling high-resolution mapping of their uptake by distinct immune and parenchymal cell populations. Our results reveal that particle size profoundly governs not only organ level distribution but also the hierarchy of cell-specific recognition and uptake. By uncovering size-governed clearance routes that operate both beyond the liver and deeper within liver microarchitecture, this study provides comprehensive mechanistic insights into the in vivo sequestration mechanisms of nanoparticles.