In principle, 
protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-
steady state conditions and with fewer off-target effects than conventional 
small molecule therapeutics. However, systemic 
protein delivery 
in vivo has been proven difficult due to poor 
tissue penetration and rapid clearance. 
Protein transduction exploits the ability of some 
cell-penetrating 
peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs—named membrane translocating sequence (MTS), membrane translocating motif (MTM) and 
macromolecule transduction domain (MTD)—are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and / or therapeutic 
efficacy of 
protein transduction. Previously, recombinant proteins consisting of 
suppressor of 
cytokine signaling 3 (SOSC3) fused to the 
fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit 
inflammation and 
apoptosis. However, this SOCS3 fusion proteins expressed in 
bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. The development of this art has been accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific 
critical factors (CFs) that affect 
intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy each critical factor. Furthermore, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance 
solubility with corresponding increases in protein yield and 
cell- / tissue-permeability. These recombinant SOCS3 proteins fused to aMTD / SD having much higher 
solubility / yield and 
cell- / tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed SOCS3 recombinant proteins fused to MTM were only tested or used as anti-inflammatory agents to treat 
acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-angiogenic agents. Since SOCS3 is known to be an endogenous inhibitor of 
pathological angiogenesis, we reasoned that iCP-SOCS3 could be used as a protein-based 
intracellular replacement therapy for inhibiting 
angiogenesis in 
tumor cells. The results demonstrated in this art support this following reasoning: 
Cancer treatment with iCP-SOCS3 results in reduced endothelial cell viability, loss of 
cell migration potential and suppressed vascular 
sprouting potentials. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, 
macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide 
novel protein therapy against 
cancer cell-mediated 
angiogenesis.