DNAzyme hydrogels specifically inhibit the NLRP3 pathway to prevent radiation-induced skin injury in mice

Radiation-induced skin injury (RISI) is a common adverse effect of radiotherapy, yet current preventive measures remain insufficient. Our previous studies have consistently highlighted the potential of biomaterials and hydrogels in mitigating RISI. Based on an extensive review of the literature, we hypothesize that NLRP3 overexpression is a key driver in the pathogenesis of RISI. Consequently, we focused on developing DNAzyme (DZ)-loaded hydrogels specifically targeting NLRP3 to prevent RISI.
To this end, we designed and optimized NLRP3-DZ using AZ 960 bioinformatics tools, molecular dynamics simulations, and gel electrophoresis analysis. We then encapsulated the NLRP3-DZ within ZIF-8 nanoparticles to improve its stability, controlled release, and biocompatibility. To enhance transdermal delivery and practical application, we further conjugated the system with the TAT transmembrane peptide, resulting in the final construct: NLRP3-DZ@ZIF-8/TAT.
In vitro experiments demonstrated that DZ-hydrogels are highly biocompatible, efficiently suppress NLRP3 expression, promote cell migration, inhibit apoptosis, and exhibit antibacterial activity. Transcriptomic analyses indicated that these effects may be mediated by modulating key mRNA signaling pathways.
Additionally, in a murine model of RISI, the material accelerated wound healing by regulating proteins involved in apoptosis, oxidative stress, and inflammation. Collectively, these findings offer promising insights into the potential of DZ-hydrogels for the effective prevention of RISI.