Messenger RNA (mRNA) is a key molecule of life. Theoretically, it can encode any protein the human body requires, making it a "universal key" for treating virtually all protein-based diseases. However, the journey of mRNA drug development has been far from smooth: mRNA was first discovered in 1961, and in 1990, the Jon Wolff laboratory at the University of Wisconsin first reported that in vitro-transcribed (IVT) mRNA injected into mice elicited an immune response. Yet it was not until the COVID-19 pandemic that mRNA technology was first applied in humans—in December 2020, the world's first mRNA vaccine BNT162b2 received Emergency Use Authorization (EUA) in the U.K., followed by full approval from the U.S. Food and Drug Administration (FDA) in August 2021 for COVID-19 prevention.

From animal experiments to human application, mRNA drugs—despite their immense potential—have encountered numerous obstacles over half a century. What has hindered their progress?

mRNA molecules are large and negatively charged, preventing free passage through biological membranes. They are easily degraded by RNases in plasma and tissues, rapidly cleared by the liver and kidneys, and recognized by the immune system—resulting in short half-lives. After cellular entry, they often become "trapped" in endosomes, unable to function properly. These biological barriers stand like the "Maginot Line" on the path to mRNA drug development.

In summary, the bottlenecks and challenges in mRNA drug development focus on two main areas:

1. How to prevent mRNA from being cleared and degraded after entering the body.
2. How to enhance transmembrane capability and precise targeting.

Addressing instability is the primary hurdle. Through chemical modification—including modifications to the 5' cap, poly(A) tail, 5' and 3' UTRs, and the coding region—mRNA molecules can "trick" the body's defense systems, prolonging exogenous mRNA activity and preventing degradation.

Achieving efficient delivery is the second major challenge. Modified mRNA must cross the lipid membrane barrier to reach the cytoplasm and be translated into functional proteins. Currently, the most common approach is to encapsulate mRNA in stable lipid nanoparticles, including lipoplexes (LP) , lipopolyplexes (LPR) , Lipid Nanoparticles (LNP) , and cationic nanoemulsions (CNE) —enabling efficient in vivo delivery, which is critical for therapeutic relevance.

"With perseverance, even stone can be pierced." Behind the seemingly simple words "synthesis" and "delivery" lies decades of dedication and effort. Every exploration deserves respect, and every innovation deserves recognition.