Targeted drug delivery to endothelial cells utilizing functionalized nanocarriers (NCs) is an essential procedure in therapeutic and diagnosis therapies. Using dissipative particle dynamics simulation, NCs have been designed and combined with an endothelial environment, such as the endothelial glycocalyx (EG) layer, receptors, water, and cell wall. Furthermore, the energy landscapes of the functionalized NC with the endothelial cell have been analyzed as a function of properties such as the shape, size, initial orientation, and ligand density of NCs. Our results show that an appropriate higher ligand density for each particular NC provides more driving forces than barriers for the penetration of the NCs. Herein we report the importance of shell entropy loss for the NC shape effect on the adhesion and penetration into the EG layer. Moreover, the rotation of the disc shape NC as a wheel during the penetration is an extra driving force for its further inclusion. By increasing the NCs' size larger than the appropriate size for each particular ligand density, due to an increase in the NCs' shell entropy loss, the barriers surpass the driving forces for NC penetration. Furthermore, the parallel orientation provides the NCs with the best penetration capabilities. However, the rotation of the disc shape NCs enhances their diffusion in the perpendicular orientation too. Overall, our findings highlight the crucial role of the shell entropy loss in governing the penetration of NCs. Besides, studying NCs with a homogeneous ligand composition enabled us to cross barriers and probe energetics after the complete inclusion of the NCs.