Lipid nanoparticles (LNPs) are a critical structural element of modern mRNA therapeutics, including COVID‑19 modRNA vaccines. Each formulation is a multicomponent system in which the LNP serves not as a passive carrier but as an active, biointeractive entity whose ionizable lipids engage directly with cellular membranes. Current evidence from cellular, transcriptomic, and proteomic analyses indicates that LNPs, with or without active mRNA cargo, alter transcriptomic programs and protein expression. This suggests that, even during uptake and interaction with the membrane (transfection), the membrane serves as an initial site for inflammatory, detoxifying, and stress responses. Simultaneously, pathways involved in fat metabolism and detoxification are affected, such as the peroxisome proliferator-activated receptor γ (PPARγ) and cytochrome P450 (CYP) enzyme systems. We believe that the phosphatidylinositol (PI) cycle is the initial point for these disorders. This cycle regulates both organelle trafficking and membrane restructuring following endocytic processes, including macropinocytosis. When this cycle is disrupted, membrane restructuring and organelle dysfunction occur, triggering downstream signaling cascades such as nuclear factor kappa-B (NF- κB), mitogen-activated protein kinases (MAPKs), Janus kinase–signal transducer (JAK-STAT) pathways, and mechanistic target of rapamycin (mTOR) complexes. Transfection with LNPs may induce a systemic condition we call lipid-nanoparticle-driven membrane dysfunction (L‑DMD), where transfection results in broader dysregulation of cellular communication, stress response, and energy balance. This hypothesis-driven review offers a mechanistic foundation for understanding the diffuse, often enduring, biological effects observed after exposure to messenger RNA LNP formulations. It highlights a needed perspective at the intracellular level and within systems biology.
Seger et al. (Fri,) studied this question.