p65 siRNA-Loaded Buformin/DNA Nanoprisms Alleviate Acute Lung Injury through Inhibiting NLRP3-Mediated Pyroptosis

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome are triggered by complicated molecular mechanisms, which are the prime causes of high mortality in critical patients. Recent research suggests that the release of high levels of IL-1β and IL-18, resulting from pyroptosis, plays a pivotal role in causing cytokine storms that lead to severe respiratory damage. DNA nanostructures possess desirable properties, such as biocompatibility, programmability, biodegradability, and nontoxicity, making them suitable for use as drug delivery vehicles. In this study, it has been found that the DNA nanoprism acts as a carrier to deliver buformin, which serves as not only a mediator for DNA assembly but also a drug that inhibits NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis. To enhance the therapeutic effect of buformin, six p65 siRNA molecules are loaded onto the DNA nanoprism. Both buformin and p65 siRNA demonstrated remarkable inhibition of NLRP3-mediated pyroptosis. Furthermore, the synergistic effect of the p65 siRNA-loaded buformin/DNA nanoprism in reducing inflammation levels by inhibiting pyroptosis was investigated in both an in vitro model of macrophage cell pyroptosis and an in vivo model of ALI mice. In conclusion, this DNA nanoplatform has the potential to change the future treatment of ALI as it carries two therapeutic agents simultaneously, resulting in synergistic therapeutic effects. This proposed approach offers new strategies that could enhance the overall effectiveness of the ALI treatment.