Update publication information. Nanoparticle elasticity plays crucial roles in determining nanoparticles’ physiological performances. However, the underlying mechanisms by which nanoparticle elasticity does so remain unknown.Using core-shell nanoparticles with a same PEGylated lipid bilayer shell yet cores differing in elasticity (45 kPa – 760 MPa) as the models, we isolated the effects of nanoparticle elasticity from those of other physiochemical parameters and observed a surprisingly non-monotonic relationship of nanoparticle elasticity versus nanoparticle systemic circulation lifetime, which segmented into three distinct regions depending on nanoparticle elasticity.