Colon-Accumulated Gold Nanoclusters Alleviate Intestinal Inflammation and Prevent Secondary Colorectal Carcinogenesis via Nrf2-Dependent Macrophage Reprogramming

Abstract

Inflammatory bowel disease (IBD) is one of the main factors leading to colitis-associated colorectal cancer (CAC). Therefore, it is critical to develop an effective treatment for IBD to prevent secondary colorectal carcinogenesis. M2 macrophages play crucial roles in the resolution phase of intestinal inflammation. However, traditional drugs rarely target intestinal M2 macrophages, and they are not easily cleared. Gold nanoclusters are known for their in vivo safety and intrinsic biomedical activities. In this study, a glutathione-protected gold nanocluster is synthesized and evaluated, namely, GA. Interestingly, GA specifically accumulates in the colon during IBD. Furthermore, GA not only promotes M2 differentiation of IL-4treated peritoneal macrophages but also reprograms macrophage polarization from M1 to M2 in a pro-inflammatory environment. Mechanistically, this regulatory effect is exerted through activating the antioxidant Nrf2 signaling pathway, but not traditional STAT6. When applied in IBD mice, we found that GA elevates M2 macrophages and alleviates IBD in an Nrf2-dependent manner, evidenced by the abolished therapeutic effect upon Nrf2 inhibitor treatment. Most importantly, GA administration significantly suppresses AOM/DSS-induced CAC, without causing obvious tissue damage, providing critical evidence for the potential application of gold nanoclusters as nanomedicine for the treatment of IBD and CAC.

Sishen Pill and its active phytochemicals in treating inflammatory bowel disease and colon cancer: an overview

“…Under normal physiological conditions, the Nrf2 in cells binds to the kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm and remains in a steady state; when Keap1 receives an oxidative stress signal, it can release Nrf2 and then transfer it to the nucleus and upregulate the expression of downstream antioxidant proteins, such as HO-1 ( Ibrahim et al, 2023 ). At the same time, HO-1 can also block the NF-κB activation and downregulate the transcription of inflammatory factors and chemokines by inhibiting the production of cytokines and ROS ( Wang and He, 2022 ); this may contribute to the treatment of IBD by inhibiting intestinal inflammation-cancer transformation ( Lu et al, 2023 ).…”

Nanotechnology in inflammation: cutting-edge advances in diagnostics, therapeutics and theranostics

“…Remarkably, GA exhibited targeted accumulation in the colon. GA not only facilitated M2 differentiation of IL-4-treated peritoneal macrophages but also shifted macrophage polarization from M1 to M2 in a pro-inflammatory setting 239 .…”

“…The outcomes demonstrated that the Au NP was more effective in reducing tissue degeneration and inhibiting the p38α enzyme compared to standard Captopril therapy 238 . Shifting macrophage polarization from M1 to M2 plays key roles in resolving inflammation 239 . Lu et al invented glutathione-protected gold nanoclusters (GA) for treating IBD 239 .…”

“…Shifting macrophage polarization from M1 to M2 plays key roles in resolving inflammation 239 . Lu et al invented glutathione-protected gold nanoclusters (GA) for treating IBD 239 . Remarkably, GA exhibited targeted accumulation in the colon.…”

Competitive coordination assembly of light-degradable gold nanocluster-intercalated metal organic frameworks for photoresponsive drug release

“…Glutathione-capped gold nanoclusters were chosen as luminescent materials because of their abundant surface functional groups ( e.g. , the carboxyl and amino groups), good biocompatibility 12 and small average size. 13 ZIF-8 was selected as a carrier with high surface area, good stability, and negligible cytotoxicity.…”