A Nanoparticle Platform For Improved Potency, Stability, And Adjuvanticity Of Poly(I:C)

Cancer immunotherapies and prophylactic vaccines against infectious diseases often exploit adjuvants such as toll-like receptor agonists (TLRa) to drive potent and directed immune responses. Unfortunately, a promising class of TLRa based on nucleic acid derivatives is susceptible to degradation by nucleases, cause life-threatening systemic toxicities, and is difficult to target to specific cell populations or tissues within the body. In this study a library of cationic polymeric nanoparticles (NP) is developed for encapsulation and delivery of the double-stranded RNA structural mimic, poly(I:C) (pIC), to address these limitations. Using a combinatorial library screening approach, pIC/poly(beta-amino ester) (PBAE) NPs are identified that skew activation resulting in enhanced potency (13-fold increase in type I interferon [IFN] production) and negligible toxicity. These highly potent adjuvant NPs increase the magnitude, duration, and affinity maturation of antigen-specific antibodies following vaccination with a model subunit vaccine. This NP platform provides an opportunity to alter the immune response to pIC, creating a potent type I IFN-producing adjuvant capable of driving stronger humoral responses to immunization and improving affinity maturation more than 14-fold. This platform can be applied generally to develop more effective vaccines and immunotherapies.