An Immunomodulatory DNA Hydrogel Based on Tetrahedral Framework Nucleic Acids for Treating Psoriasis

Psoriasis represents a persistent immune-mediated dermatological disorder for which no curative therapy is currently available, imposing a considerable burden on affected individuals and healthcare resources. And aberrant macrophage activation is one of the main factors influencing the course of psoriasis. However, safe and drug-free strategy to modulate macrophages is still urgently needed. Here, we developed a tetrahedral framework DNA-based hydrogel (TDH), which was constructed via the self-assembly of sticky-ended tetrahedral DNA nanostructures (TDNs). TDH exhibited robust mechanical strength, injectability, and self-healing properties, demonstrating advantages over conventional DNA hydrogels. TDH markedly downregulated pro-inflammatory cytokine and chemokine levels in macrophages activated by lipopolysaccharide (LPS). Furthermore, a widespread reprogramming of inflammatory signaling networks was shown by transcriptome analysis. Clinical symptoms were significantly reduced by topical TDH application in an imiquimod-induced psoriasis mouse model <i>in vivo</i>, which also decreased the infiltration of immune cells and both epidermal hyperplasia, and successfully resulted in immune homeostasis. Importantly, this effect was achieved without systemic toxicity. Collectively, this study establishes TDH as a biocompatible, programmable, and drug-free immunoregulatory platform, which provides a strategy for the application of nucleic acid-based biomaterials in dermatological therapy.