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(β‐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.