(534g) Invited Talk: Evaluating Design Parameters for Aerosol Immune Engineering Using Polymeric and Metal-Organic Framework Nanoparticles

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 to treat asthma and have yet to effectively address many significant respiratory conditions, including COVID-19. A critical need remains to expand inhaled drug delivery beyond the limited number of current therapeutics. Towards this need, we are evaluating a range of nanoparticle platforms as inhalable therapeutics that can more efficiently direct innate immune responses within the lung, leading to more effective inhalable vaccines and immune-modulatory therapeutics. Using poly(ethylene glycol) diacrylate (PEGDA)-based chemistries to access tunable physiochemical properties of size, charge, and degradation rate, we sought to characterize the cellular distribution of these model PEGDA NPs in specialized antigen presenting cell (APC) populations within the lung. Cationic and anionic formulations of PEGDA NPs were fabricated with similar hydrodynamic diameters around ~225 nm and low polydispersity indexes and formulated as aerosols using both nebulization and dry powder formulation approaches. We have assessed in vitro NP distribution of nebulized NPs onto immune cells cultured at the air-liquid interface (ALI), as well as in vivo to varied pulmonary APC populations following orotracheal instillation in young (~3 months) and old (~14 months) C57BL/6 mice. Cellular uptake in immune cell subpopulations, NP trafficking, and the cellular inflammatory profiles were compared between the two groups for each of the particle formulations, suggesting distinct design rules for the different age groups, corresponding to differences in protein corona compositions. Building on these fundamental studies, we designed metal-organic framework (MOF) NPs containing aluminum (Al) to serve as inhalable vaccine adjuvants that could similarly traffic to key pulmonary APC populations. We find that Al-MOFs exhibit robust adjuvanticity at lower Al dosing than the standard alum vaccine formulations, along with superior aerosol characteristics. Overall, this work provides advances towards personalized inhaled particulate formulations, with potential future applications for novel treatments of COVID-19, cancer, inflammation, vaccination, and allergy.