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2025 ; 16
(1
): 9205
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Enhancing cap-independent translation of linear mRNA
#MMPMID41102175
Golojuch S
; Largey B
; El-Sagheer AH
; Brown T
Nat Commun
2025[Oct]; 16
(1
): 9205
PMID41102175
show ga
While cap-dependent translation remains the primary focus in mRNA-based
therapeutics, cap-independent translation holds promise for targeting diseases
ranging from cancer to neurodegeneration. However, cap-independently translated
mRNAs are unstable, produce less protein than capped mRNAs, and current methods
for their improvement are imperfect. Here, we propose the use of in vitro
transcription priming with azido-modified dinucleotide primer and
post-transcriptional modification utilising click chemistry to improve the
properties of cap-independently translated mRNAs. Our results demonstrate a
significant enhancement in mRNA stability and protein output without eliciting
immunogenicity. Moreover, we show how the mRNA 5'-end modification strategy can
be used to investigate transfection and cap-independent translation processes in
cells overcoming burdens associated with previous methods. Together, our findings
support cap-independent translation as a viable alternative to the established
cap-dependent process and provide tools for further exploration and enhancement
of this modality.
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