Enhanced gene transfection efficacy and safety through granular hydrogel mediated gene delivery process

Although gene therapy has made great achievements in both laboratory research and clinical translation, there are still challenges such as limited control of drug pharmacokinetics, acute toxicity, poor tissue retention, insufficient efficacy, and inconsistent clinical translation. Herein, a gene therapy gel is formulated by directly redispersing polyplex nanoparticles into granular hydrogels without any gelation pre-treatment, which provides great convenience for storage, dosing and administration. In vitro studies have shown that use of granular hydrogels can regulate the gene drug release, reduce dose dependent toxicity and help improve transfection efficacy. Moreover, the developed gene therapy gel is easy to operate and can be directly used in vitro to evaluate its synergistic efficacy with various gene delivery systems. As such, it represents a major advance over many conventional excipient-based formulations, and new regulatory strategies for gene therapy may be inspired by it. Statement of significance: A gene therapy gel is formulated by assembly of polyplex nanoparticles and granular hydrogels, which not only exhibits synergistic properties of controlled drug release, low cytotoxicity and high transfection efficacy, but provides great convenience for drug storage, dosing and administration. Moreover, depending on the applied load, the gene therapy gel can present either “solid-like” or “liquid-like” rheological response, allowing rapid drug application to lesion followed by efficient drug retention. As such, the gene therapy gel represents a major advance over many conventional excipient-based formulations and new gene delivery strategies may be inspired by it.