Delivering mRNA drugs effectively into the human body is highly challenging. mRNA is a large, negatively charged single-stranded molecule—and the cell membrane is also negatively charged, creating electrostatic repulsion that hinders cellular entry. mRNA is inherently fragile and rapidly degraded by various enzymes in the body.

Yet mRNA must be delivered into cells to encode proteins and exert therapeutic effects. How to deliver mRNA to target cells in sufficient quantity with sufficiently high translation efficiency is a critical challenge and a core hurdle in mRNA formulation.

Key barriers include extracellular barriers, endosomal escape, and intracellular immunity.

Extracellular barriers are the first hurdle. mRNA, composed of hundreds to thousands of nucleotides, is too large for free diffusion across cell membranes. Its half-life of approximately 7 hours is short—it is rapidly degraded by serum RNases before reaching target cells. Negative charges on both mRNA and cell membranes further impede entry via electrostatic repulsion.

After crossing extracellular barriers and entering target cells via endocytosis, mRNA must escape from endosomes to bind ribosomes and be translated into antigenic proteins—which are then modified and secreted to exert function.

As a foreign nucleic acid, mRNA activates the innate immune system and pro-inflammatory cytokine expression, promoting cellular or humoral responses. However, intracellular immunity can also degrade mRNA before it is translated into therapeutic protein.

To overcome these barriers—delivering mRNA to sufficient numbers of target cells with adequate translation levels—highly specific and efficient mRNA delivery systems are essential. This remains a key technical challenge in mRNA drug development. Various materials have been explored, including lipids, lipid-like materials, polymers, inorganic materials, cell membranes, and hybrid systems. Among current mainstream delivery systems, Lipid Nanoparticles (LNPs) are the most advanced and clinically validated.