Rett Syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females. The disease is mainly caused by pathogenic variants in the X-linked MECP2 gene, which encodes for the global transcriptional regulator MeCP2, important for neuronal maturation and maintenance. So far, no cure is currently available. Recently, cell penetrating peptides (CPPs) attracted a special interest in the use of protein replacement therapy by facilitating the transport of proteins across cell membranes and the blood-brain barrier (BBB).In this study, we generated a neuronal cell model by direct reprogramming of RTT patient fibroblasts to test the efficacy of a potential RTT protein replacement therapy. Therefore, recombinant MeCP2 was tethered to the CPP TAT, a small peptide derived from the HIV-1 "trans-activator of transcription" protein to investigate transduction ability and therapeutic effects in RTT neurons.We found that treatment with TAT-MeCP2 ameliorated hyperacetylation of H4K16 in MeCP2-deficient neurons, a hallmark of abolition of MeCP2 function. Moreover, our treatment scheme alleviated morphological deficits and affected the transcriptome of MeCP2 deficient neurons.Taken together, direct reprogramming of RTT patient fibroblasts into neurons provide a powerful tool to study disease mechanisms and recombinant TAT-MeCP2 can ameliorate the phenotype of this neuronal cell model.