Programmable soft DNA hydrogels stimulate cellular endocytic pathways and proliferation

Hydrogels are pivotal in tissue engineering, regenerative medicine, and drug delivery applications. Existing hydrogel platforms are not easily customizable and often lack precise programmability, making them less suited for 3D tissue culture and programming of cells. DNA molecules stand out among other promising biomaterials due to their unparalleled precision, programmability, and customization. In this study, we introduced a palette of novel cellular scaffolding platforms made of pure DNA-based hydrogel systems while improving the shortcomings of the existing platforms. We showed a quick and easy one step synthesis of DNA hydrogels using thermal annealing based on sequence specific hybridization strategy. We also demonstrated the formation of multi-armed branched supramolecular scaffolds with custom mechanical stiffness, porosity, and network density by increasing or decreasing the number of branching arms. These mechanically tuneable DNA hydrogels proved to be a suitable suitable platform for modulating the physiological processes of retinal pigment epithelial cells (RPE1). In-vitro studies showed dynamic changes at multiple levels, ranging from a change in morphology to protein expression patterns, enhanced membrane traffic, and proliferation. The soft DNA hydrogels explored here are mechanically compliant and pliable, thus excellently suited for applications in cellular programming and reprogramming. This research lays the groundwork for developing a DNA hydrogel system with a higher dynamic range of stiffness, which will open exciting avenues for tissue engineering and beyond.