The mechanical properties of submicron particles offer a unique design space for advanced drug-delivery particle engineering. However, the recognition of this potential is limited by a poor consensus about both the specificity and sensitivity of mechanosensitive endocytosis over a broad particle stiffness range. In this report, our model series of polystyrene-co-poly(N-isopropylacrylamide) (pS-co-NIPAM) microgels have been prepared with a nominally constant monomer composition (50 mol % styrene and 50 mol % NIPAM) with varied bis-acrylamide cross-linking densities to introduce a tuned spectrum of particle mechanics without significant variation in particle size and surface charge. While previous mechanosensitive studies use particles with moduli ranging from 15 kPa to 20 MPa, the pS-co-NIPAM particles have Young's moduli (E) ranging from 300 to 700 MPa, which is drastically stiffer than these previous studies as well as pure pNIPAM. Despite this elevated stiffness, particle uptake in RAW264.7 murine macrophages displays a clear stiffness dependence, with a significant increase in particle uptake for our softest microgels after a 4 h incubation. Preferential uptake of the softest microgel, pS-co-NIPAM-1 (E = 310 kPa), was similarly observed with nonphagocytic HepG2 hepatoma cells; however, the uptake kinetics were distinct relative to that observed for RAW264.7 cells. Pharmacological inhibitors, used to probe for specific routes of particle internalization, identify actin- and microtubule-dependent pathways in RAW264.7 cells as sensitive particle mechanics. For our pS-co-NIPAM particles at nominally 300-400 nm in size, this microtubule-dependent pathway was interpreted as a phagocytic route. For our high-stiffness microgel series, this study provides evidence of cell-specific, mechanosensitive endocytosis in a distinctly new stiffness regime that will further broaden the functional landscape of mechanics as a design space for particle engineering.

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