Injectable Supramolecular Hydrogels as Delivery Agents of Bcl‐2 Conversion Gene for the Effective Shrinkage of Therapeutic Resistance Tumors

Injectable hydrogels to deliver therapeutic genes in a minimally invasive manner and to achieve long term sustained release at tumor sites to minimize side effects are attractive for cancer therapy and precision medicine, but its rational design remains a challenge. In this report, an injectable supramolecular hydrogel system is designed based on the polypesudorotaxane formation between α‐cyclodextrin (α‐CD) and cationic methoxy‐poly(ethylene glycol)‐ b ‐poly(ε‐caprolactone)‐ b ‐poly(ethylene imine) (MPEG–PCL–PEI) copolymer, with the ability to form polyplexes with anionic plasmid DNA for effective sustained gene delivery. To be mentioned, the MPEG–PCL–PEI copolymers show similar pDNA binding ability, better gene transfection efficiency, lower cytotoxicity than nonviral gene transfection gold standard PEI (25 kDa), due to the formation of micelles and more stable polyplexes. More importantly, this MPEG–PCL–PEI/α‐CD/pDNA supramolecular hydrogel shows a sustained release of pDNA in form of polyplex for up to 7 d. By taking these advantages, this supramolecular hydrogel system is applied as an injectable carrier for sustained Bcl‐2 conversion gene release, in an in vivo rodent model of therapeutic resistant hepatocarcinoma with high expression of antiapoptotic Bcl‐2 protein. This work represents the first time that injectable MPEG–PCL–PEI/α‐CD supramolecular hydrogels possess good controllable release effect of Bcl‐2 conversion genes in the form of polyplex to effectively inhibit in vivo tumor growth and this “enemy to friend” strategy will benefit various applications, including on‐demand gene delivery and personalized medicine.