Developments in mRNA/lipid nanoparticle (LNP) technology have advanced the fields of vaccinology and gene therapy, raising questions about immunogenicity. While some mRNA/LNPs generate an adjuvant-like environment in muscle tissue, other mRNA/LNPs are distinct in their capacity for multiple rounds of therapeutic delivery. We evaluate the adjuvancy of components of mRNA/LNPs by phenotyping cellular infiltrate at injection sites, tracking uptake by immune cells, and assessing the inflammatory state. Delivery of 9 common, but chemically distinct, LNPs to muscle revealed two classes of inflammatory gene expression programs: inflammatory (Class A) and noninflammatory (Class B). We find that intramuscular injection with Class A, but not Class B, empty LNPs (eLNPs) induce robust neutrophil infiltration into muscle within 2 h and a diverse myeloid population within 24 h. Single-cell RNA sequencing revealed SM-102-mediated expression of inflammatory chemokines by myeloid infiltrates within muscle 1 day after injection. Surprisingly, we found direct transfection of muscle infiltrating myeloid cells and splenocytes 24 h after intramuscular mRNA/LNP administration. Transfected myeloid cells within the muscle exhibit an activated phenotype 24 h after injection. Similarly, directly transfected splenic lymphocytes and dendritic cells (DCs) are differentially activated by Class A or Class B containing mRNA/LNP. Within the splenic DC compartment, type II conventional DCs (cDC2s) are directly transfected and activated by Class A mRNA/LNP. Together, we show that mRNA and LNPs work synergistically to provide the necessary innate immune stimuli required for effective vaccination. Importantly, this work provides a design framework for vaccines and therapeutics alike.