mRNA vaccines have been proven to be highly effective; however, they are often more reactogenic than several older platforms, and systemic symptoms can limit their acceptance. Lipid nanoparticles (LNPs) are at the center of this tradeoff; they enable mRNA delivery, while also providing adjuvant-like innate stimulation. In this review, we summarize recent progress in understanding how LNPs shape innate immune sensing and inflammatory signatures and how these responses relate to adjuvanticity and reactogenicity. We discuss why LNP adjuvanticity is not a single fixed property; different formulations can elicit distinct innate programs, and consequently, different profiles of adjuvanticity and reactogenicity. In addition, the possibility that adjuvanticity and reactogenicity may be partially uncoupled is discussed. Even if the mechanisms driving inflammatory responses and adjuvanticity are not fundamentally distinct, these outcomes may diverge depending on when, where, and how strongly innate signals are triggered, which can be tuned through formulation, including the control of in vivo distribution. Finally, we outline the design principles and experimental requirements for linking LNP behavior to specific pathways and outcomes, enabling safer and more effective LNP-based vaccines. These insights support a rational formulation to expand future vaccine options.
