This study presents a thermodynamic model for receptor-mediated endocytosis of ligand-coated nanoparticles (NPs). The model identifies an optimal NP radius (25–30 nm) at which cellular uptake reaches a maximum of several thousand under physiologically relevant conditions. The model shows that NP uptake is regulated by membrane tension and can be controlled by particle size. The optimal radius is consistent with prior estimates. The model considers the thermodynamic equilibrium of a cell immersed in a solution with dispersed ligand-coated NPs, where the chemical potential difference drives the system to equilibrium. The model accounts for the binding of NPs to the cell membrane through specific interactions and the resulting wrapping and endocytosis of NPs. The model also considers the energy landscape of NP wrapping, including bending and stretching energies, and the effects of membrane tension on the wrapping process. The model predicts that the cellular uptake depends on the particle size, with optimal uptake occurring at a radius of approximately 25 nm. The model also shows that the cellular uptake is influenced by the surface concentration of NPs and membrane tension. The model is validated against experimental data, showing good agreement with the observed cellular uptake of NPs in various cell types. The study highlights the importance of particle size in determining the efficiency of NP endocytosis and provides insights into the design of NP-based drug delivery systems. The model also suggests that the optimal NP radius falls within the size range of typical viruses, indicating broad implications for materials design principles. The study concludes that the optimal NP radius for maximal cellular uptake is approximately 25 nm, which is important for the rational design of NP-based cellular delivery systems.This study presents a thermodynamic model for receptor-mediated endocytosis of ligand-coated nanoparticles (NPs). The model identifies an optimal NP radius (25–30 nm) at which cellular uptake reaches a maximum of several thousand under physiologically relevant conditions. The model shows that NP uptake is regulated by membrane tension and can be controlled by particle size. The optimal radius is consistent with prior estimates. The model considers the thermodynamic equilibrium of a cell immersed in a solution with dispersed ligand-coated NPs, where the chemical potential difference drives the system to equilibrium. The model accounts for the binding of NPs to the cell membrane through specific interactions and the resulting wrapping and endocytosis of NPs. The model also considers the energy landscape of NP wrapping, including bending and stretching energies, and the effects of membrane tension on the wrapping process. The model predicts that the cellular uptake depends on the particle size, with optimal uptake occurring at a radius of approximately 25 nm. The model also shows that the cellular uptake is influenced by the surface concentration of NPs and membrane tension. The model is validated against experimental data, showing good agreement with the observed cellular uptake of NPs in various cell types. The study highlights the importance of particle size in determining the efficiency of NP endocytosis and provides insights into the design of NP-based drug delivery systems. The model also suggests that the optimal NP radius falls within the size range of typical viruses, indicating broad implications for materials design principles. The study concludes that the optimal NP radius for maximal cellular uptake is approximately 25 nm, which is important for the rational design of NP-based cellular delivery systems.