RNA interference (RNAi) has emerged as an approach to treating many diseases, including myocardial infarction, wherein pathologic gene targets that are pathogenic can be silenced through small interfering RNAs (siRNAs) or microRNAs (miRNAs). RNAi technologies have gained popularity as therapeutics due to their ability to efficiently silence the expression of complementary gene targets at the translational level, often times enabling inhibition of targets that small molecules or other therapeutics would be incapable of targeting. For myocardial infarction, many targets for RNAi have emerged, which represent exciting therapeutic avenues that are still clinically unaddressed.

Hydrogels, water-swollen polymer networks, have developed in parallel as bulking agents for myocardial infarction with several formulations being investigated in clinical trials. In addition, hydrogels are widely used as drug delivery vehicles, where they can localize and sustain the release of encapsulated therapeutics to their target tissue. Towards the application of RNAi in the heart, hydrogels enable RNAi through local and sustained delivery, while minimizing off-target effects and serum instability.

This dissertation describes the engineering of three different injectable hydrogel RNAi delivery platforms after myocardial infarction, investigating these systems both in vitro and in vivo, both generally as platform delivery vehicles, and applied with specific goals of improving cardiomyocyte regeneration and tissue remodeling.

The first system is a guest-host assembled hyaluronic acid hydrogel that releases cholesterol-modified miRNA mimics to promote cardiomyocyte proliferation. The second system is a guest-host assembled polyethylenimine hydrogel that enhances uptake of siRNAs by releasing them as polyplexes, which are active in vitro and in vivo. The third system is a hyaluronic acid hydrogel assembled through dynamic covalent hydrazone bonds for injection that sequesters and releases siRNA to attenuate cardiac remodeling. Finally, we evaluate techniques toward percutaneous delivery and imaging of said hydrogel RNAi delivery platforms for the translation of these systems into large animals and humans.