The importance of physico-chemical characteristics such as size, shape and surface chemistry on nanocarrier cellular uptake and in vivo tumour accumulation is widely recognized. On the other hand, the effect of nanocarrier elasticity remains poorly studied, due to the difficult task of suitably modulating this property without affecting other parameters.
Now, Guo et al. address this challenge by synthesizing nanoparticles made of an external layer of liposomes and an alginate hydrogel core. This composition allows production of nanoparticles with homogeneous size and surface chemistry, controlled by the lipid bilayer, and variable elasticity. The addition of different concentrations of calcium chloride during the nanoparticle preparation leads to different extents of alginate crosslinking, which influences the stiffness of the material. The resulting nanoparticles display a range of elasticities, measured in terms of Young’s moduli, varying from 45 kPa to 19 MPa. In cellular uptake studies, the researchers show an inverse correlation between nanoparticle elasticity and internalization, with the softer nanoparticles, consisting only of the liposome shell, more readily internalized by both normal and cancer cells. Using fluorescence microscopy, they demonstrate that soft nanoparticles enter the cells by fusing with the cell membrane, while stiffer nanoparticles penetrate via endocytosis, a longer and energetically more expensive process that requires membrane bending, nanoparticle engulfment, endosome formation and release within the cell. Since delivery to the endosome might trigger nanoparticle degradation, tuning the elasticity of nanomaterials to promote direct cytoplasmic delivery via fusion should be beneficial for intracellular delivery.