Cell-Dependent Phagocytosis of Nonspherical Nanoparticles Enables Selective Immune Targeting

Controlling the physicochemical properties of nano/microparticles is key to optimizing their performance as drug carriers and achieving selective uptake by target cells. Despite abundant experimental evidence that particle shape plays a major role in cellular uptake (phagocytosis) with varying cell-dependent trends, the physical principles governing shape-dependent engulfment remain poorly understood. Therefore, the design of nanoparticles in biomedicine relies heavily on brute force experiments, suffering from low efficiency without suitable predictive models. Here, we present a theoretical model estimating the active energy required to overcome the energy barrier posed by cell membrane deformation and particle adhesion. We systematically investigate this activation energy under varying particle and cell properties, thus inferring the phagocytic efficiency . Our results reveal that rod-like particles are strongly favored to achieve phagocytosis under conditions of low membrane tension or weak adhesion, whereas disk-like shapes are preferred under high tension or strong adhesion. These predictions align with in vitro and in vivo observations: stiffer macrophages phagocytose rod-shaped particles less effectively, while neutrophils preferentially internalize rod-like particles. Additionally, we also note the importance of particle concentration on the particle shape effect. Despite existing at a dilute concentration on the cell surface, the particle-induced membrane shape changes are not local and are strongly coupled to the phagocytosis efficiency. This work provides a quantitative framework for designing shape-optimized particles to control cellular interaction outcomes and enable selective targeting of specific cell types.