Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated chronic inflammatory diseases that mainly affect the ileum, rectum, and colon. These diseases cause various symptoms, such as abdominal pain, diarrhea, and bloody stools.[1] In recent years, the prevalence of IBDs has substantially increased in many regions, which could pose a significant social and economic burden on governments and healthcare systems in the future.[2] Although the exact causes of IBDs are not yet fully understood, studies suggest that changes in the intestinal microbiome and excessive oxidative stress leading to intestinal barrier dysfunction play critical roles in the pathogenesis of IBDs.[[3], [4], [5], [6], [7]] Although several traditional clinical drugs, such as immunosuppressants, steroids, 5-aminosalicylic acid (5-ASA) drugs, and biological agents, are available to treat IBDs, these drugs primarily relieve symptoms but do not address the underlying issues associated with the intestinal flora and oxidative stress.[[8], [9], [10]] Furthermore, their prolonged use can lead to severe side effects, such as intestinal immune disorders, increased risk of infections, and even death from intestinal pathogens. This may be due to the nonselective nature of these drugs.[11,12] Studies have shown that an imbalance in the intestinal flora, characterized by an increase in the abundance of facultative anaerobic Enterobacteriaceae bacteria and a decrease in the abundance of beneficial bacteria, tends to damage the intestinal barrier, thereby increasing the risk of microbial invasion and an abnormal immune response.[[13], [14], [15], [16], [17], [18]] Therefore, several microbiome regulation therapeutics have been developed to actively regulate the composition of gut bacteria to promote intestinal mucosal repair and treat IBDs.[6,19,20]

In addition, excessive oxidative stress, particularly RONS in the gut, plays a crucial role in the development and progression of colitis. In IBDs, RONS induce the production of nitrates, S-oxides, and n-oxides, which serve as a source of terminal electron acceptors for anaerobic respiration in Proteobacteriaceae, leading to the expansion of the abnormal flora of the obligate anaerobic Enterobacteriaceae.[21] Additionally, obligate anaerobic probiotics are vulnerable to RONS, allowing harmful Enterobacteriaceae to occupy this niche.[7,22] In addition, RONS cause nonspecific damage to colon tissues by attacking proteins, DNA, and lipids.[23] As a result, drugs with a single microbiome regulation effect are often not very effective. In the search for drugs that can simultaneously regulate the microbiome while eliminating RONS, we are targeting a wide range of functional nanomedicines. Currently, nanomaterials have been engineered for treating IBDs by targeting excessive oxidative stress or pathogenic bacteria to modulate dysfunctional gut microbiota. Nevertheless, there is a scarcity of literature on treating IBDs through the reprogramming of Enterobacteriaceae in the inflamed gut and the clearance of RNOS.[[24], [25], [26], [27], [28], [29], [30], [31], [32]] Thus, a multifunctional nanomaterial that can reprogram the gut microbiome and eliminate RONS during inflammation is necessary. These nanomaterials can restore gut homeostasis and effectively treat IBDs.

To meet the demand for an effective treatment for IBD, ultrasmall coordination polymer nanodots have been synthesized using GA (gallic acid) and tungsten (W), a polyphenolic organic compound and a multifunctional metal that regulates the microbiome through the inhibitory action of Enterobacteriaceae in response to outbreaks of inflammation.[28,33,34] However, GA and other natural antioxidants have limited capacity to balance intestinal homeostasis due to their instability under harsh conditions, poor pharmacokinetics, high water solubility, potential toxicity at high doses, and nonspecific tissue accumulation.[35,36] To address these limitations and develop a fully functional nanomedicine for IBDs, we aimed to enhance the tungsten (W) defects in RONS removal by combining it with natural products such as GA. In this platform, the GA segment not only reduces RONS damage to colon tissue but also protects the tungsten-reprogrammed flora from stressors. Highly dispersed nanodots with RONS removal capabilities were formed after modification with PVP and coordination of W to GA. Specifically, these nanodots showed scavenging ability against nitrogen free radicals (with ABTS and DPPH) and oxygen free radicals (in MB experiments), as well as superoxide dismutase (SOD)-mimicking activity, which relieved inflammatory symptoms. Moreover, the nanodots acted as protectors for obligate anaerobic probiotics, shielding the tungsten-reprogrammed bacteria from oxidative damage and facilitating the rapid re-establishment of intestinal barrier function. In a DSS-induced model of acute colitis, W-GA nanodots reduced RONS levels, decreased the production of related inflammatory factors, and increased the expression of proteins associated with intestinal tight junctions, thereby restoring intestinal barrier function. Ultimately, the mice were protected from weight loss, shortened colon length and tissue damage. Most importantly, W-GA nanodots, which can be synthesized using a straightforward method and are not significantly toxic either in vitro or in vivo, play a significant role in the reconstruction of the intestinal barrier in colitis. This has led to the expanded application of industrial inorganic metal coordination natural products in clinical settings.