Versatility of mRNA reprogramming by targeted SMaRT. The figure shows a schematic of splicing reactions involving a three-exon pre-mRNA and PTMs. A conventional constitutive cis-splicing reaction leading to the production of the expected 1•2•3 mRNA is shown (i). Three targeted SMaRT reactions are shown. PTM[A] contains a functional 5′ splice site that can trans-splice to the 3′ splice site adjacent to exon 2 in the pre-mRNA target (ii). This trans-splicing produces a chimeric A•2•3 mRNA. PTM[A] is targeted to occlude the naturally occurring 5′ splice site at exon 1 to reduce the use of this site. PTM[C] contains a functional 3′ splice site that can trans-splice to the 5′ splice site adjacent to exon 2 in the pre-mRNA target (iii). This trans-splicing produces a chimeric 1•2•C mRNA. Finally, PTM[B] contains both 3′ and 5′ splice sites bordering an exon, and these splice sites can trans-splice with the 5′ splice site adjacent to exon 1 and the 5′ splice site adjacent to exon 3, respectively (iv). These two trans-splicing reactions lead to internal exon replacement and produce the chimeric 1•B•3 mRNA.