Sepsis is a clinical syndrome characterized by acute systemic inflammatory response accompanied by multiple organ dysfunction and failure, with a mortality rate of up to 17% -26% [1]. Diabetes is one of the most important risk factors of sepsis, which has been demonstrated to affect the onset and prognosis of sepsis [2,3]. Accumulating evidence suggest that sepsis patients with diabetes have high risk to develop acute liver and renal failure within 72 h of hospital admission, which is significantly associated with high mortality [4]. The pathogenesis of both diabetes and sepsis involve excessive inflammatory response and oxidative stress, which could be superposed upon the co-occurrence of these two diseases [2,5]. Consequently, amplified production of inflammatory factors, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), as well as elevated levels of reactive oxygen species (ROS) can cause severe damage to different organs including liver and kidney, ultimately leading to multiple organ damage or failure [6], [7], [8], [9]. Treatments with cytokine or pathogen recognition receptors (PRRs) antagonists show favorable results in the anti-inflammatory treatment of sepsis [10], yet, lack of multiple roles and specificity to the kidney and liver, as well as severe side effects of these antagonists largely limit their clinical application to different types of sepsis [11], [12], [13].

Nanomedicine has emerged as an outstanding candidate for targeted treatment of various diseases [14], [15], [16], [17], [18], [19], [20], [21], effectively improving the therapeutic effects while reducing the side effects of different drugs [22,23]. Its capability to engineer molecules at the sub micrometer scale allows it to construct attractive multifunctional materials for diverse bioapplications [22,24,25]. Especially, DNA-based nanomedicine exhibits excellent biocompatibility and low immunogenicity, which has been widely utilized in the treatment of various diseases such as acute kidney injury [24,26,27], liver fibrosis [28], cancer [29,30], and rheumatoid arthritis [31]. Among those DNA nanostructures, the rectangular DNA origami nanostructure (rDON) has shown the ability to precisely load biomolecules on its surface [32], [33], [34], and mainly accumulates in the kidney and liver [27], emphasizing its therapeutic potential in various kidney and liver related diseases. Additionally, rDON, in common with other DNA nanostructures, presents potent antioxidant activities, which serve as the ideal candidate to scavenge excessive ROS produced in SUDC [24,26,35].

In this study, we design a DNA-based, bifunctional nanomedicine, termed IL10-rDON, to preferentially accumulate in kidney and liver for anti-inflammation and ROS scavenging in SUDC. IL10-rDON is a two-dimensional planar DNA nanostructure composed of a rectangular DNA origami nanostructure (rDON) and interleukin 10 (IL10). It bears two distinct functional elements. The first functional element in IL10-rDON is rDON, which has the ability to preferentially accumulate in the kidney and liver. This enables the maximum delivery of therapeutic agents directly to the renal and hepatic sites, while minimizing the potential side effects on other organs. rDON are also sensitive to various ROS and can be utilized as an effective ROS scavenger. The second functional element is anti-inflammatory element that utilizes IL10 as a powerful immune modulator for anti-inflammation and tissue regeneration. The in vivo experiments demonstrated that IL10-rDON sufficiently attenuated the increased levels of ROS and inflammation at the kidney and liver injury sites and prevented the kidney and liver injury. IL10-rDON treatment also effectively improved liver and renal function, as well as the survival rate of mice with SUDC. This study demonstrates IL10-rDON as an attractive antioxidant and anti-inflammatory nanomedicine for addressing acute liver and renal failure. Furthermore, this DNA-based nanomedicine holds immense potential for extensive utilization in treating multi-organ failure under certain pathological conditions.