Intestinal immune homeostasis and microbiome structure play a critical role in the pathogenesis and progress of inflammatory bowel disease (IBD), whereas IBD treatment remains a challenge as the first‐line drugs show limited therapeutic efficiency and great side effect. In this study, a colon‐targeted adhesive core–shell hydrogel microsphere is designed and fabricated by the ingenious combination of advanced gas‐shearing technology and ionic diffusion method, which can congregate on colon tissue regulating the gut immune‐microbiota microenvironment in IBD treatment. The degradation experiment indicates the anti‐acid and colon‐targeted property of the alginate hydrogel shell, and the in vivo imaging shows the mucoadhesive ability of the thiolated‐hyaluronic acid hydrogel core of the microsphere, which reduces the systematic exposure and prolongs the local drug dwell time. In addition, both in vitro and in vivo study demonstrate that the microsphere significantly reduces the secretion of pro‐inflammatory cytokines, induces specific type 2 macrophage differentiation, and remarkably alleviates colitis in the mice model. Moreover, 16S ribosomal RNA sequencing reveals an optimized gut flora composition, probiotics including Bifidobacterium and Lactobacillus significantly augment, while the detrimental communities are inhibited, which benefits the intestinal homeostasis. This finding provides an ideal clinical candidate for IBD treatment.

ALKBH5 maintains CD4 ⁺ T cell pathogenicity during autoimmune disease via regulating IFN-γ and CXCL2.

Inflammatory bowel disease (IBD) affects millions of people each year. The overproduction of reactive oxygen species (ROS) plays a critical role in the progress of IBD and will be a potential therapeutic target. Here, we synthesize a kind of oral zero-valent-molybdenum nanodots (ZVMNs) for the treatment of IBD by scavenging ROS. These ultrasmall ZVMNs can successfully pass through the gastric acid and then be absorbed by the intestine. It has been verified that ZVMNs can down-regulate the quantity of ROS and reduce colitis in a mouse IBD model without distinct side effects. In addition, RNA sequencing reveals a further mechanism that the ZVMNs can protect colon tissues from oxidative stress by inhibiting the nuclear factor κB signaling pathway and reducing the production of excessive pro-inflammatory factors. Together, the ZVMNs will offer a promising alternative treatment option for patients suffering from IBD.

The functional integrity of CD8⁺ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8⁺ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8⁺ T cell metabolic state and antitumor functions. SENP7-deficient CD8⁺ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8⁺ T cell–derived ROS triggered cytosolic SENP7–mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell–intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8⁺ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8⁺ T cell metabolic fitness and effector functions and unveil an oxidative stress–sensing machinery in tumor-infiltrating CD8⁺ T cells.

Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over‐stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti‐thrombosis and anti‐inflammation competency is developed to impede this cycle, cross‐linked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP‐Ag‐BSA, exhibits excellent self‐healing ability, injectability, biocompatibility, and sustained drug release. HEP‐Ag‐BSA also demonstrates anti‐coagulation and anti‐inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP‐Ag‐BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP‐Ag‐BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the “inflammation and microthrombosis” cycle, providing a novel integrated approach against IBD.