Particle geometry governs protein corona-mediated neutrophil hitchhiking for enhanced tumor delivery

Abstract

Particle geometry can alter nanomedicine transport, yet its intrinsic contribution is difficult to define because shape engineering usually changes particle composition or surface chemistry. Here we use sonication to transform compositionally identical SN38 dimeric prodrug nanoassemblies from spheres into rods with aspect ratios of 6, 9 and 40. Geometry remodelled the plasma protein corona and directed the nanoassemblies towards distinct transport routes. Spheres and AR40 rods tent to recruit complement or acute-phase proteins and suffered from quick clearance in vivo, whereas AR9 rods enriched transport proteins, prolonging circulation but remaining largely confined to tumor perivascular regions. AR6 rods minimized complement deposition and enriched neutrophil‑associated proteins, resulting in sustained neutrophil hitchhiking, high tumor accumulation, and efficient delivery into the tumor parenchyma. At 12 h, AR6 rods achieved 29-fold greater tumor accumulation than compositionally identical spheres. AR6 rods exhibited the greatest antitumor efficacy in both CT26 colorectal and 4T1 breast tumor models, which are characterized by neutrophil enrichment. These findings identify particle geometry as a programmable regulator of nanoparticle transport in vivo and establish a general strategy for geometry engineering that preserves chemical composition, providing new design principles for next-generation nanomedicines.