Polyoxazoline‐Based Gene Delivery System Mediated Tumor Vascular Normalization and Extracellular Matrix Degradation to Inhibit Cancer Growth, Recurrence, and Metastasis

Abstract Gene therapy has brought hope for curing major diseases including cancer. However, an efficient and safe delivery system is key for successful gene therapy. In this study, PPERD (i.e., OHC‐PEG‐CHO/PEtOx 0.2 ‐PEI 0.73 ‐PRGD 0.07 /DNA), polyoxazoline‐based gene delivery system is developed to mediate tumor vascular normalization and extracellular matrix (ECM) degradation for cancer therapy. The aldehyde groups of OHC‐PEG‐CHO can form Schiff base bonds with the amine groups of PER (i.e., PEtOx 0.2 ‐PEI 0.73 ‐PRGD 0.07 ), thereby enabling in situ encapsulation of PERD (i.e., PER/DNA) and rapid pH responsiveness in tumor tissues. PPERD possesses an excellent in vitro transfection performance and good biocompatibility. PPERD can efficiently accumulate, penetrate, and transfect in tumors once intravenous administration. PPERD effectively normalizes tumor vasculature and degradates ECM, enhances the infiltration and function of cytotoxic T lymphocytes, thereby inducing an antitumor immune response in vivo. Moreover, PPERVH ((i.e., OHC‐PEG‐CHO/PEtOx 0.2 ‐PEI 0.73 ‐PRGD 0.07 /(pshVEGF+pHAase)) can also efficiently inhibit cancer recurrence and metastasis by triggering durable anti‐tumor immune memory effect. Furthermore, PPERVH significantly enhances the effectiveness of immune checkpoint blockade‐mediated immunotherapy. This gene therapy strategy provides a promising paradigm for inhibiting cancer growth, recurrence, and metastasis.