Expanding Chemical Space of Nucleic Acid Nanoparticles for Tunable Antiviral‐Like Immunomodulatory Responses and Potent Adjuvant Activity

The rise of personalized medicine demands affordable biomaterials with tunable physicochemical properties, biological activities, and immune responses. We introduce a nucleic acid nanoparticle (NANP)-based platform designed to engage with the human immune system in a controllable manner. By varying the chemical composition while keeping the architectural parameters constant, we identified key factors that influence the immunorecognition and stability of NANPs. Chemical modifications provide additive functional regulation, while pairing NANPs with different delivery agents further enhances their immunomodulatory capabilities. Specific compositions boost T cell effector functions, promote B cell proliferation, and activate innate immune populations in human peripheral blood mononuclear cells. The resulting interferon responses and immune signatures mimic those triggered by viral infections. Notably, in vivo studies demonstrate that NANPs function as efficiently as traditional clinically used adjuvants, without increasing the risk of autoimmunity. This suggests that NANPs are a safe and effective tool for immunotherapy with promise for developing formulations targeting cancer and infectious diseases.