Engineering nanoparticle interactions with innate immune cells to develop pulmonary therapeutic vehicles and cell therapies
Date
2022
Authors
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Publisher
University of Delaware
Abstract
Macrophages, a class of tissue resident innate immune cells, are responsible for sequestering foreign objects through the process of phagocytosis, making them a promising target for immune modulation via particulate engineering. Macrophage-based cell therapy has been identified as a promising therapeutic approach to treat cancers and immune dysfunctions, owing to the functionality and phenotype plasticity of macrophages. However, current attempts of macrophage activation for autologous cell therapy fail to elicit effective therapeutic responses because of low cell survival ex vivo following macrophage isolation from tissue and upon reintroduction. The effect of nanoparticle (NP) internalization on cell fate has emerged as an important consideration for nanomedicine design, as macrophages and other phagocytes are primary clearance mechanisms of administered NP formulations. In this dissertation, we report that NP dosing and cellular internalization via phagocytosis significantly enhances survival of ex vivo cultures of primary bone marrow-derived, alveolar, and peritoneal macrophages over particle-free controls. The enhanced survival is attributed to suppression of caspase-dependent apoptosis and is linked to phagocytosis and lysosomal signaling. Uniquely, poly(ethylene glycol)-based NP treatment extended cell viability in the absence of macrophage polarization and enhanced expression of pro-survival B cell lymphoma-2 (Bcl-2) protein in macrophages following multiple routes of in vivo administration. The enhanced survival phenomenon is also applicable to NPs of alternative chemistries, indicating the potential universality of this phenomenon with relevant drug delivery particles. ☐ These observations have opened the door to explorations of NP physiochemical properties aimed at tuning the NP-driven macrophage survival at the lysosomal synapse. Thus, 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 is 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. Furthermore, we evaluated the effect of degradable NP dosing on the survival and activation of macrophage transplants in murine lungs and demonstrated that NP-treated macrophage transplants show superior survival and activation profiles compared to their untreated counterparts. These findings provide a framework for extending the lifespan of primary macrophages ex vivo for drug screening, vaccine studies, and cell therapies and has implications for any in vivo particulate immune-engineering applications. Furthermore, our results provide insight on tuning NP physiochemical properties as design handles for maximizing macrophage longevity.
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Keywords
Cell therapies, Macrophage, Nanoparticles, Phagocytosis, Survival