Myocarditis After mRNA Vaccination: A Metabolic–Innate Immune Cascade Centered on Lipid Nanoparticles

Figures

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  Figure 1. Proposed multi‐hit pathophysiological model of mRNA vaccine‐associated myocarditis. The model integrates several key events. LNP accumulation and metabolic disruption: Intramuscularly injected LNPs distribute to the heart, where they accumulate in endothelial cells and cardiomyocytes, disrupting fatty acid metabolism and causing mitochondrial injury. DAMP signaling and inflammatory amplification): Damaged mitochondria release DAMPs, such as cardiolipin, which, along with the LNP itself, activate innate immune sensors (TLRs, NLRP3), leading to a surge in pro‐inflammatory cytokines. Amplifying factors: This cascade is modulated by host susceptibility factors, including genetics (e.g., HLA type, immune/metabolic gene polymorphisms) and hormones (e.g., testosterone), which determine the final clinical outcome. This figure illustrates the LNP‐centered pathway that is the focus of this review. It should be noted that there are additional mechanisms that might operate in parallel or predominant in some patient subsets (Table 2).

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  Figure 2. Spatiotemporal biodistribution and persistence of mRNA–LNP components after intramuscular dosing (conceptual). (A) IM depot drains to lymph nodes and blood, producing transient systemic exposure with trace heart delivery (peak ~2–4 h). (B) Qualitative time‐course at the heart contrasts rapid clearance of mRNA and translated protein with the longer‐tail persistence of ionizable lipids. The curves are schematic and do not represent measured concentrations at clinical vaccine doses. (C) Within cardiac tissue, uptake is enriched in endothelium and resident macrophages relative to cardiomyocytes. Curves/bars are schematic (not measured values); organ‐ and chemistry‐specific kinetics are simplified.

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  Figure 3. Chemical structures of ionizable lipids and cardiolipin. (A) SM‐102, the ionizable lipid used in the Moderna (mRNA‐1273) vaccine. (B) ALC‐0315, the ionizable lipid used in the Pfizer‐BioNTech (BNT162b2) vaccine. (C) Cardiolipin, a key phospholipid of the inner mitochondrial membrane. The synthetic ionizable lipids (A, B) possess a tertiary amine headgroup (cationic at endosomal pH) and two acyl chains. In contrast, cardiolipin (C) has a diphosphate headgroup (anionic at physiological pH, charge ≈ −2) and four acyl chains. These fundamental differences in charge, headgroup chemistry, and geometry make a direct molecular mimicry between them unlikely.