Synergistic protein-reinforced DNA hydrogels with tunable biomechanics for mechanoresponsive drug release

DNA hydrogels are widely explored in biomedical research for their programmability and soft tissue-mimicking mechanics. However, their application in load-bearing implants is restricted by insufficient mechanical robustness, especially for mimicking the biomechanics of the nucleus pulposus, which is a naturally occurring functional tissue essential for spinal flexibility and shock absorption in the intervertebral disk. Here, we report a novel single-pot, two-step fabrication strategy in which long DNA strands produced by rolling circle amplification form an initial viscoelastic network that is subsequently reinforced through controlled thermal self-assembly of proteins, physically stapling the DNA chains into a mechanically tunable hybrid matrix. This synergistic protein reinforcement enables precise control over the morphological and mechanical properties of DNA hydrogels while improving stability under enzymatic and pH stress. The reinforced hydrogels maintain structural integrity under complex deformation and sustained compression in ex vivo nucleus pulposus models and exhibit pressure-dependent drug release. Overall, this study establishes protein reinforcement within viscoelastic gel networks as a distinct materials design strategy for creating programmable biomaterials that integrate molecular precision with mechanical resilience for use in mechanically demanding biological environments.