Optimization of the cell permeability of NIP-2 proved most feasible by point mutation rather than through appending a cell-penetrating peptide. The mutation approach has various advantages such as reduced toxicity and a more straightforward synthesis in comparison to preparing conjugates with CPPs. Using the most optimal NIP-2-H27A-N3 peptide we could demonstrate that poly(A) removal by the CCR4-NOT complex can indeed be affected by NOT9 targeting inhibitors in the cellular environment as treatment led to an increase of the maximum poly(A) tail length of NR4A1 and RHOB. The nuclear receptor NR4A1 plays a role in DNA repair mechanisms and increasing its levels has been proposed as a therapeutic strategy in the treatment of various aging related diseases such as diabetes, Parkinson and cardiovascular disease. The small GTPase RHOB has been described as a tumor suppressor and increasing its levels could therefore be beneficial in cancer. Both examples highlight that modulating poly(A) tail length could pose a novel therapeutic strategy that has remained unexplored.