Mesoscopic-scale insights into cellular internalization of deformable polymeric nanoparticles: Structural...

Optimizing nanomaterial properties and functions through modulating physicochemical properties within polymeric nanoparticles (NPs) has been a cornerstone of materials science and bio-nanotechnology. However, this paradigm has yet to be firmly established for broadly defined composite polymeric NPs, where the multiscale structure-function relationships governing bio-nano interactions remain largely unknown. Herein, we cultivated a large-scale mesoscopic simulation to examine the cellular internalization of deformable polymeric NPs with varying structural heterogeneity and networked elasticity. Membrane rupture occurred in homogeneous polymeric NPs with a volume swelling ratio of 5.0-12.5 %, while membrane wrapping was discovered in heterogeneous polymeric NPs during cellular internalization. Heterogeneous architectures with high Young's modulus resist deformation and induce enhanced rotational membrane perturbations, thereby promoting membrane wrapping and increasing NP uptake. In this case, heterogeneous polymeric NPs, such as core-shell and Janus-shaped NPs, have a 1.7-2.3-fold higher membrane penetration efficiency than homogeneous polymeric NPs. Furthermore, increasing networked elasticity enhances membrane wrapping efficiency by promoting stronger adhesion and resisting structural deformation, as further supported by AFM observations. Importantly, the structural deformation of polymeric NPs impedes cellular internalization via compressed surface adsorption on the membrane; however, this can be compensated for by regulating the internal structural heterogeneity that leads to membrane bending. These findings enhance our understanding of the synergistic influence of structural heterogeneity and networked elasticity on bio-nano interactions, paving the way for the development of more effective nanomaterials for targeted delivery and immune evasion.