The study investigates the potential of using the HIV-1 Tat protein to deliver heterologous proteins into cells. Tat, a protein from human immunodeficiency virus 1, can efficiently enter cells when added exogenously. The researchers chemically cross-linked Tat peptides (residues 1–72 or 37–72) to β-galactosidase, horseradish peroxidase, RNase A, and domain III of Pseudomonas exotoxin A (PE). These chimeras were effective in delivering the "cargo" proteins to various cell types and tissues in mice, with high levels in the heart, liver, and spleen and low-to-moderate levels in the lung and skeletal muscle. The primary target within these tissues was likely endothelial cells, Kupffer cells, and/or splenic macrophages. The study demonstrates that Tat-mediated uptake allows the therapeutic delivery of macromolecules that were previously thought to be impermeable to living cells, opening up new possibilities for intracellular therapeutic applications.The study investigates the potential of using the HIV-1 Tat protein to deliver heterologous proteins into cells. Tat, a protein from human immunodeficiency virus 1, can efficiently enter cells when added exogenously. The researchers chemically cross-linked Tat peptides (residues 1–72 or 37–72) to β-galactosidase, horseradish peroxidase, RNase A, and domain III of Pseudomonas exotoxin A (PE). These chimeras were effective in delivering the "cargo" proteins to various cell types and tissues in mice, with high levels in the heart, liver, and spleen and low-to-moderate levels in the lung and skeletal muscle. The primary target within these tissues was likely endothelial cells, Kupffer cells, and/or splenic macrophages. The study demonstrates that Tat-mediated uptake allows the therapeutic delivery of macromolecules that were previously thought to be impermeable to living cells, opening up new possibilities for intracellular therapeutic applications.