Understanding the endocytic process of nanoparticles (NPs) with different mechanical rigidities is critical to develop effective drug delivery vectors. Here, we perform experiments, coarse-grained molecular dynamics simulations, and theoretical analyses to investigate the role of NPs' mechanical rigidity in the cellular endocytic process. Experiments based on two types of engineered Au NPs that have similar properties but different rigidities are performed in order to investigate their cellular uptake efficiencies, and it has been found that the more rigid NPs can achieve a higher cellular uptake efficiency. Simulation results confirm that rigid NPs can achieve full internalization by forming a complete double-layer endosome coating, while relatively soft NPs can only reach 40% surface coverage by membrane lipids. Simulation results capture an intriguing translocation of multiple NPs with different rigidities in a cooperative manner where the NPs' mechanical rigidities regulate their translocation efficiencies. We find that theoretically rigid NPs require less energy to overcome the energy barrier for membrane internalization than soft NPs do, which is in good agreement with experiment and simulation results. This synergetic study offers useful insight into the design principle of a general NP-based drug delivery vector as well as the promising biomedical application of NP-based medicine.