Hydrogel nanoparticle degradation influences the activation and survival of primary macrophages

The effect of nanoparticle (NP) internalization on cell fate has emerged as an important consideration for nanomedicine design, as macrophages and other phagocytes are the primary clearance mechanisms of administered NP formulations. Pro-survival signaling is thought to be concurrent with phagocytosis and recent work has shown increased macrophage survival following lysosomal processing of internalized NPs. These observations have opened the door to explorations of NP physiochemical properties aimed at tuning the NP-driven macrophage survival at the lysosomal synapse. Here, we report that NP-induced macrophage survival and activation is strongly dependent on NP degradation rate using a series of thiol-containing poly(ethylene glycol) diacrylate-based NPs of equivalent size and zeta potential. Rapidly degrading, high thiol-containing NPs allowed for dramatic enhancement of cell longevity that was concurrent with macrophage stimulation after 2 weeks in ex vivo culture. While equivalent NP internalization resulted in suppressed caspase activity across the NP series, macrophage activation was correlated with increasing thiol content, leading to increased lysosomal activity and a robust pro-survival phenotype. Our results provide insight on tuning NP physiochemical properties as design handles for maximizing ex vivo macrophage longevity, which has implications for improving macrophage-based immune assays, biomanufacturing, and cell therapies.