Controlled Release of Poly(U) via Acetalated Dextran Microparticles for Enhanced Vaccine Adjuvant Delivery

Abstract Diverse drug delivery systems are needed to address challenges in delivering novel vaccine components and enhancing their efficacy. Poly(U) is a single-stranded RNA composed of uracil repeats that acts as a toll-like receptor (TLR) 7/8 agonist, stimulating the innate immune system. However, poly(U) is susceptible to ribonuclease degradation without a delivery carrier, and its negative charge hinders cellular uptake. Encapsulation in acetalated dextran (Ace-DEX), a pH-sensitive, biodegradable polymer, addresses these challenges. This study encapsulated poly(U) into Ace-DEX Microparticles (MPs) with either spherical (smooth MPs) or collapsed-surface (wrinkled MPs) via spray-drying. It was hypothesized that the different morphologies of MPs would influence the vaccine efficacy after in vitro and in vivo models. Smooth poly(U) MPs had a higher percent viability and cytokine response in dendritic cells (DCs) than wrinkled poly(U) MPs. Moreover, mice vaccinated with smooth poly(U) MPs + ovalbumin (OVA) showed enhanced IL-2 production and IFN-γ in response to OVA peptide and MHC-I immunodominant peptide restimulation, respectively, compared to wrinkled poly(U) MPs. However, mice vaccinated with wrinkled poly(U) MPs + OVA significantly increased B-cell and germinal center B-cell frequencies compared to mice vaccinated with phosphate buffered saline (PBS) whereas mice vaccinated with smooth poly(U) MPs + OVA did not. Overall, these findings suggest that smooth poly(U) MPs modulated dendritic cells and T-cells, and wrinkled poly(U) MPs modulated B-cells. Understanding how morphology influences these cell types will aid in optimizing future vaccine systems for more specific cellular targeting. Competing Interest Statement The authors have declared no competing interest.