Size and softness synergy in cellular microgel uptake: a force spectroscopy study

Poly(<i>N</i>-isopropylacrylamide) (PNIPAM) microgels hold promise for various biomedical applications, yet the mechanisms governing microgel interactions with cells remain poorly understood. Recent studies have highlighted the influence of cross-linker content and microgel size on cellular uptake. In this study, we employed atomic force microscopy to systematically investigate the internal structure of both conventional and ultralow cross-linked (ULC) PNIPAM microgels physically adsorbed at the glass/water interface. By studying the correlation between the degree of microgel deformation on a rigid substrate and their stiffness, measured <i>via</i> force spectroscopy, we developed a characterization method that predicts microgel uptake ability in HEK293T cells. Notably, our findings extend to micron-sized ULC microgels, validating the proposed concept. Together, our approach enables the prediction of cellular internalization across a wide range of microgel types, potentially streamlining the screening of crucial microgel properties during early synthesis stages, prior to extensive cell interaction experiments.