Targeted drug delivery using functionalized nanocarriers (NCs) presents a powerful approach to enhancing therapeutic precision by leveraging receptor-ligand interactions on cell surfaces. However, achieving optimal NC binding remains a challenge due to the complex interplay of receptor density, ligand affinity, membrane mechanics, and NC properties. This study investigates how these factors collectively influence multivalent interactions, aiming to identify tunable parameters for optimizing NC adhesion. We employ a multiscale computational framework integrating Monte Carlo simulations and thermodynamic analysis to explore the effects of receptor expression levels, receptor-ligand interaction strengths, and membrane mechanics on the binding of NCs with distinct mechanical properties—rigid, semi-rigid, and flexible. Our findings reveal that: (1) receptor density modulates multivalent binding cooperativity, with higher densities amplifying ligand-receptor engagement; (2) ligand affinity plays a crucial role in stabilizing NC attachment, with stronger interactions promoting avidity while weaker interactions enable dynamic exchange; and (3) membrane mechanics significantly alter binding free-energy landscapes, with excess area-driven fluctuations either enhancing or hindering NC attachment depending on NC rigidity. The findings of this work contribute to the rational engineering of functionalized carriers, advancing targeted therapeutic and diagnostic applications in complex biological environments.
