The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of chimeric polynucleotide molecules, which allow for customized placement, position and percent load of chemical modifications, which improve, alter or optimize certain physicochemical and pharmaceutical properties of the polynucleotides. In one non-limiting embodiment, such chimeric polynucleotides take the form or function as modified mRNA molecules which encode a polypeptide of interest. In one embodiment, such chimeric polynucleotides are substantially noncoding.