The present invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides comprising at least one terminal modification. Described herein are polynucleotides comprising at least one terminal modification, methods, processes, kits and devices using the polynucleotides comprising at least one terminal modification in one or more untranslate regions. Such untranslated regions may be a 5′ or 3′ untranslated region.