Coordinated gene-catalytic therapy to attenuate intervertebral disc degeneration: A beehive-like nucleic acid nanozyme for microenvironment modulation.

Intervertebral disc degeneration (IVDD) is a prevalent global health issue that imposes a significant socio-economic burden. Currently, effective treatments are lacking due to the intractable microenvironment and poor drug retention. Chronic oxidative stress and unrelenting inflammation remain the primary therapeutic targets. Here, we developed a beehive-like nucleic acid framework (TRC) for combined gene-catalytic therapy. This beehive-like nucleic acid framework was hierarchically constructed by utilizing tetrahedral framework nucleic acids (tFNAs) as modular building blocks, which were interconnected by miR-129-5p "bridges" to form a stable, hollow-chambered framework (TR). This architecture facilitated the high-density sequestration of CeO₂ nanozymes within its structural frameworks. To ensure durable efficacy, the beehive-like nucleic acid framework was encapsulated within a stimuli-responsive, self-reinforced dual-network hydrogel (HTRC) to prevent leakage and mechanical collapse while enabling on-demand release. Mechanistically, HTRC attenuated IVDD by orchestrating a hierarchical cargo protection and responsive delivery: CeO₂ nanozymes restored redox homeostasis, while miR-129-5p reprogrammed cells towards an anabolic phenotype by suppressing MAPK and NF-κB pathways. In conclusion, the HTRC platform successfully reconstructed a pro-regenerative microenvironment and alleviated discogenic pain, offering a promising paradigm for attenuating intervertebral disc degeneration.