The efficient delivery of biologics into cells provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. The supercharged polypeptide (SCP) has become a novel intracellular delivery system due to their special advantages, including enhanced delivery efficiency and serum tolerance. However, owing to their cationic charge and non-specificity characteristics, the in vivo application of SCP is limited. Here, an activatable SCP (ASCP) with a pH-sensitive charge shielding sequence (CSS), a protease cleavage site, and SCP are engineered. This system shows the potential to reduce the non-specific binding and effectively deliver various cargo (peptide, protein, small molecule, and siRNA) into the cytosol not only in vitro but also in vivo. Furthermore, an ASCP fusion protein is designed to co-delivery of peptide (KLA)/siRNA (IKBKE) with different tumorigenesis pathways to triple negative breast cancer (TNBC) for optimal therapeutic outcomes. It is believed that ASCP delivery system will facilitate the development of bioactive molecules for use against intracellular targets. This simple yet versatile delivery system can also pave the way for the co-delivery of multiple therapeutic cargos to address the emerging needs of combination cancer therapy.