Deformation-Induced Enthalpy-Entropy Competition Governs Cellular Penetration of Elastic Polymer Nanoparticles:...

The mechanical elasticity of polymeric nanoparticles (NPs) critically governs their interactions with biological membranes, yet the coupled thermodynamic-dynamic mechanisms remain insufficiently resolved. Here, a molecular thermodynamic-dynamic (MTD) framework integrating coarse-grained molecular dynamics, umbrella sampling, well-tempered metadynamics, and transition-state theory is established to elucidate elasticity-regulated penetration. NP deformability drives an enthalpy-entropy competition that shapes depth-dependent free-energy landscapes and translocation behavior. Soft NPs (<100 kPa) exhibit enthalpy-dominated attractions and metastable interfacial wetting that hinder penetration, whereas hard NPs (>1 MPa) display entropy-driven profiles, reduced enthalpic contributions, and accelerated, deeper translocation accompanied by membrane wrapping. Intermediate NPs display a temperature-driven enthalpy-entropy crossover. Dynamically, hard NPs translocate across membranes more rapidly and to greater depths than their soft counterparts. TEM and AFM measurements corroborate the distinct wetting and wrapping behavior. These findings establish a unified thermodynamic-dynamic paradigm for NP-membrane interactions and guide the rational design of nanocarriers.