Nucleic Acid Delivery from Granular Hydrogels

Nucleic acid delivery has applications ranging from tissue engineering to vaccine development to infectious disease. Cationic polymer condensed nucleic acids are used with surface-coated porous scaffolds and are able to promote long-term gene expression. However, due to surface loading of the scaffold, there is a limit to the amount of nucleic acid that can be loaded, resulting in decreasing expression rate over time. In addition, surface-coated scaffolds are generally non-injectable. Here, it is demonstrated that cationic polymer condensed nucleic acids can be effectively loaded into injectable granular hydrogel scaffolds by stabilizing the condensed nucleic acid into a lyophilized powder, loading the powder into a bulk hydrogel, and then fragmenting the loaded hydrogel. The resulting hydrogel microparticles contain non-aggregated nucleic acid particles, can be annealed post-injection to result in an injectable microporous hydrogel, and can effectively deliver nucleic acids to embedded cells with a constant expression rate. Due to the nature of granular hydrogels, it is demonstrated that mixtures of loaded and unloaded particles and spatially resolved gene expression can be easily achieved. The ability to express genes long term from an injectable porous hydrogel will further open the applications of nucleic acid delivery.