(232c) Nanoparticle Physiochemical Design Features to Modulate Pulmonary Innate Immune Cell Response

While respiratory diseases globally number among the top causes of mortality, the field of pulmonary drug delivery has lagged behind other routes of administration in the application of novel therapeutic approaches. Most current inhalers are employed in the treatment of asthma and have yet to effectively address many significant respiratory conditions. A significant need remains to expand inhaled drug delivery beyond the limited number of current therapeutics. Thus, the overall goal of the Fromen lab is to develop personalized aerosol immunomodulatory therapeutics for patients with a wide range of airway conditions. To overcome current challenges in the field, our group designs new approaches to therapeutic pulmonary aerosols, leveraging chemical engineering principles, immune engineering approaches, and additive manufacturing.

In this talk, I will discuss recent work from our lab to create and characterize nanoparticle therapeutics for efficient pulmonary vaccines and therapeutics. We have explored a range of new particle chemistries, including polymeric and metal organic framework (MOF) platforms, and have evaluated how various physiochemical properties, including particle degradation rate, influence innate immune responses. Interestingly, we find that the lifespan of macrophages, innate immune cells that protect the deepest regions of the lung, are highly regulated by phagocytosis of particles through anti-apoptotic and non-inflammatory mechanisms. We find that nanoparticle (NP) dosing and cellular internalization via a single phagocytosis event 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, which was also found to occur in vivo following two separate routes of administration. We find this phenomenon is applicable to NPs of alternative chemistries and varies as a function of dosing frequency and particle degradation rate, indicating the potential universality of this phenomenon with relevant drug delivery particles and the significance of using NP therapeutics to regulate cell lifespan. Overall, our efforts will continue to advance aerosol design rules to inform personalized inhaled particulate formulations, with potential future applications for novel treatments for cancer, inflammation, vaccination, and allergy.