Synthesis of a Cationic Supramolecular Block Copolymer with Covalent and Noncovalent Polymer Blocks for Gene Delivery

The design and fabrication of safe and highly efficient nonviral vectors is the key scientific issue for the achievement of clinical gene therapy. Supramolecular cationic polymers have unique structures and specific functions compared to covalent cationic polymers, such as low cytotoxicity, excellent biodegradability, and smart environmental responsiveness, thereby showing great application prospect for gene therapy. However, supramolecular gene vectors are facile to be degraded under physiological conditions, leading to a significant reduction of gene transfection efficiency. In order to achieve highly efficient gene expression, it is necessary for supramolecular gene vectors being provided with appropriate biostability to overcome various cell obstacles. To this end, a novel cationic supramolecular block copolymer composed of a conventional polymer and a noncovalent polymer was constructed through robust β-cyclodextrin/ferrocene host–guest recognition. The resultant supramolecular block copolymer perfectly combines the advantages of both conventional polymers and supramolecular polymers ranging from structures to functions. This supramolecular copolymer not only has the ability to effectively condense pDNA for enhanced cell uptake, but also releases pDNA inside cancer cells triggered by H<sub>2</sub>O<sub>2</sub>, which can be utilized as a prospective nonviral delivery vehicle for gene delivery. The block polymer exhibited low cytotoxicity, good biostability, excellent biodegradability, and intelligent responsiveness, ascribing to the dynamic/reversible nature of noncovalent linkages. In vitro studies further illustrated that the supramolecular block polymer exhibited greatly improved gene transfection efficiency in cancer cells. This work offers an alternative platform for the exploitation of smart nonviral vehicles for specific cancer gene therapy in the future.