Beyond vaccines: emerging technologies capable of unlocking the promise of biologically targeted mRNA therapeutics

Immunization requires minimal protein expression levels, while mRNA therapeutics requires a 1,000-fold-higher protein level to reach a therapeutic threshold. Efficient delivery to solid organs remains challenging. Even the tissue bioavailability, circulatory half-life, and efficiency of the LNP-based carrier could be rate-limiting when it is delivered to the target tissue. Even with optimized mRNA chemical modifications and advanced LNPs, chronic dosing eventually activates innate immunity, parallelly attenuating therapeutic protein expression.

An individual mRNA has a cap, 5′ and 3′ untranslated regions (UTRs), an open reading frame (ORF), and a polyadenylated (poly(A)) tail. There have been advancements in the design of each of these components. Most notable of these are:

i) improved 5′ cap analogs that enhance translational capacity, but more importantly, the capping efficiency from 70% to 95%.

ii) the poly(A) tail length optimization has proven critical for balancing the synthetic capability of an mRNA cargo.

iii) UTR sequence optimization could improve protein expression of an mRNA cargo by a fewfold, allowing its customization to the targeted biological area and disease-elicited microenvironment.

iv) Studies have documented 130+ naturally occurring chemical modifications for mRNA so far. The chemically modified nucleosides, particularly uridine moieties, such as methylpseudouridine, can reduce recognition by the toll-like receptors of the innate immunity by up to 100-fold, which, in turn, markedly increases protein expression after in vivo transfection of mRNA cargos. In the future, clinically effective, unmodified therapeutic mRNAs might become available that will conceal themselves from the immune system and have enhanced translational efficiency in vivo, similar to chemically modified mRNA vaccines.