AbstractPolymeric nanocarriers have a broad range of clinical applications in recent years, but an inefficient delivery of polymeric nanocarriers to target tissues has always been a challenge. These results show that tuning the elasticity of hydrogel nanoparticles (HNPs) improves their delivery efficiency to tumors. Herein, a microfluidic system is constructed to evaluate cellular uptake of HNPs of different elasticity under flow conditions. It is found that soft HNPs are more efficiently taken up by cells than hard HNPs under flow conditions, owing to the greater adhesion between soft HNPs and cells. Furthermore, in vivo imaging reveals that soft HNPs have a more efficient tumor delivery than hard HNPs, and the greater targeting potential of soft HNPs is associated with both prolonged blood circulation and a high extent of cellular adhesion.