Biophysical Considerations in the Rational Design and Cellular Targeting of Flexible Polymeric Nanoparticles

Abstract How nanoparticle (NP) mechanical properties impact multivalent ligand–receptor‐mediated binding to cell surfaces, the avidity, propensity for internalization, and effects due to crowding remains unknown or unquantified. Through computational analyses, the effects of NP composition from soft, deformable NPs to rigid spheres, effect of tethers, the crowding of NPs at the membrane surface, and the cell membrane properties such as cytoskeletal interactions are addressed. Analyses of binding mechanisms of three distinct NPs that differ in type and rigidity (core‐corona flexible NP, rigid NP, and rigid‐tethered NP) but are otherwise similar in size and ligand surface density are reported; moreover, for the case of flexible NP, NP stiffness is tuned by varying the internal crosslinking density. Biophysical modeling of NP binding to membranes together with thermodynamic analysis powered by free energy calculations is employed, and it is shown that efficient cellular targeting and uptake of NP functionalized with targeting ligand molecules can be shaped by factors including NP flexibility and crowding, receptor–ligand binding avidity, state of the membrane cytoskeleton, and curvature inducing proteins. Rational design principles that confer tension, membrane excess area, and cytoskeletal sensing properties to the NP which can be exploited for cell‐specific targeting of NP are uncovered.