Shape-Dependent Entropic Forces Govern Synergistic Bystander Nanoparticle Uptake

The rational design of multicomponent nanocarriers for synergistic drug delivery remains a central goal of nanomedicine, yet progress is often hindered by an incomplete understanding of the underlying biophysical principles. Here, we investigate the role of nanoparticle shape in ″bystander uptake″, a process where the active cellular uptake of functionalized nanoparticles (F-NPs) promotes the co-internalization of nonfunctionalized bystander nanoparticles (B-NPs). Combining experiments, simulations, and theory, we demonstrate a nonmonotonic dependence on B-NP geometry, with nanorods of aspect ratio (AR) ≈ 3 exhibiting markedly superior uptake compared to other shapes including the spherical, triangular, or plate-like counterparts. Molecular dynamics simulations reveal that this enhancement stems not from greater binding affinity but from shape-dependent entropic force that drives rapid particle reorientation, which is linked to metastable trapping in a ″staircase″ free energy landscape. Crucially, this experimentally observed optimal AR cannot be explained by single-particle models but is successfully predicted by our theoretical framework incorporating the collective action of F-NPs. This model identifies AR ≈ 3 as a ″sweet spot″ that balances entropic advantages against rotational constraints. These findings establish shape selectivity as a principle for multicomponent nanocarrier design, shifting the focus from optimizing enthalpy-modulated end-state affinity to engineering entropy-driven state transitions.