Construction of Tumor Microenvironment‐Responsive Gene Carriers

Abstract Peptide‐ and polypeptide‐based self‐assembling gene delivery systems have received considerable attention owing to their inherent biocompatibility and bioactivity. Gene carriers based on elastin‐like polypeptides (ELPs) have been extensively studied because of their controllability and unique temperature responsiveness. The (EK) 10 ‐PLGLAG‐Tat polypeptide sequence was selected for tumor gene delivery, with ELP serving as the hydrophobic core. In this sequence, a hydration layer can be formed on the surface of the carrier using the zwitterionic peptide segment (EK) 10 , which helps prevent the nonspecific adsorption of plasma proteins. Additionally, the MMP‐2 enzyme‐responsive PLGLAG peptide segment is responsible for exposing the cell‐penetrating peptide Tat specifically near tumor cells, facilitating the penetration of tumor cells. To introduce (EK) 10 ‐PLGLAG‐Tat into the self‐assembling carrier while ensuring its bioactivity, a leucine zipper ZR/ZE with opposite charges was used to link it to the ELP. Because of its high specificity and low systemic toxicity, the carrier was named environmentally responsive gene carrier (ERGV). Experimental results demonstrated that the ERGV effectively removed (EK) 10 in MMP‐2 overexpressed environments, altering the surface charge from negative to positive and facilitating ssDNA delivery into tumor cells. These findings highlight the potential of ERGVs as a safe and efficient method for targeted gene delivery to tumors.