Structure, manufacturing and uses of human-derived cell-permeable peptides conjugated with specific biologically active cargo peptides

Embodiments disclosed herein provide compositions for conjugates, including fusion proteins, and methods of using them to treat a variety of conditions. In some embodiments, the conjugates and/or fusion proteins incorporate a 60-amino acid human homeodomain (e.g., peptides derived from human HOX genes), to translocate functional and regulatory peptides and proteins or other biologically active molecules such as nucleic acids, which are not naturally associated with the human homeodomain, across cell and nuclear membranes to intended sites of action without provoking an unwanted immune response that may reduce exposure to the conjugate and/or result in a clinical adverse event. In further embodiments, disclosed conjugates and fusion proteins can pass through the blood-brain barrier to allow entry into the CNS. In various embodiments, the disclosed compositions are suitable for delivery into a cell (i) the expression product of a gene of interest and/or (ii) novel peptides or polynucleotides to regulate gene function.