Controllable Star Cationic Poly(Disulfide)s Achieve Genetically Cascade Catalytic Therapy by Delivering Bifunctional Fusion Plasmids

The absence of effective delivery vectors and suitable multifunctional plasmids limits cancer gene therapy development. The star cationic poly(disulfide)s with β‐cyclodextrin cores (termed β‐CD‐g‐PSSn) for caveolae‐mediated endocytosis are designed and prepared via mild and controllable disulfide exchange polymerization for high‐efficacy cancer therapy. Then, β‐CD‐g‐PSSn/pDNA complexes are transported to the Golgi apparatus and endoplasmic reticulum. Disulfides in β‐CD‐g‐PSSn vectors are degraded by glutathione in tumor cells, which not only promotes intracellular pDNA release but also reduces in vitro and in vivo toxicity. One bifunctional fusion plasmid pCATKR, which expresses catalase (CAT) fused to KillerRed (KR) (CATKR) in the same target cell, is also proposed for genetically cascade catalytic therapy. When compared with pCAT‐KR (plasmid expressing CAT and KR separately in the same cell), delivered pCATKR decomposes hydrogen peroxide, alleviates tumor hypoxia more effectively, generates stronger reactive oxygen species (ROS) capabilities under moderate irradiation, and leads to robust antitumor cascade photodynamic effects. These impressive results are attributed to fusion protein design, which shortens the distance between CAT and KR catalytic centers and leads to improved ROS production efficiency. This work provides a promising strategy by delivering a catalytic cascade functional plasmid via a high‐performance vector with biodegradable and caveolae‐mediated endocytosis characteristics. A bioreducible gene delivery system comprising star cationic poly(disulfide)s (β‐CD‐g‐PSSn)via a controllable disulfide exchange polymerization and bifunctional fusion plasmids (pCATKR) is constructed for genetically cascade therapy. β‐CD‐g‐PSS20 accesses tumor cells via caveolae‐mediated pathway to enhance gene expression. The fusion protein CATKR expressed by β‐CD‐g‐PSS20/pCATKR improves ROS production and treatment effects compared with the non‐fusion protein CAT‐KR expressed by β‐CD‐g‐PSS20/pCAT‐KR.