Impact of Network Functionalization on the Surface Properties and Behavior of Thermoresponsive Copolymeric Nanogels

We use molecular dynamics simulations to explore how the spatial distribution of N -isopropylacrylamide (NIPAm) units in copolymer nanogels with ethylene glycol (EG) affects their thermoresponsive behavior. Three functionalization strategies are explored: random, core, and surface distribution of NIPAm, with varying monomer fractions and cross-linking densities. These nanogels deswell with increasing temperature, while lower cross-linking density enhances network flexibility and improves thermoresponsiveness. The volume phase transition temperature (VPTT) and degree of deswelling depend strongly on NIPAm distribution and content. Core-functionalized nanogels show a VPTT similar to pure pNIPAm systems, while random and surface distribution shift it to higher temperatures. Surface-functionalized nanogels form hydrophobic NIPAm patches and Janus-like structures that expose EG segments at physiological temperature, tunable via composition and cross-linking density. These results demonstrate that nanogel architecture can be tailored to control internal reorganization and surface hydrophilicity, enabling the design of advanced thermoresponsive nanocarriers.