Inulin‐Based Oral Chemotherapy Modulates Gut Microbiota and Immune Microenvironment through Inhibition of Neutrophil Extracellular Trap Formation for Improving Cancer Therapy

Despite the potential of chemoimmunotherapy against colorectal cancer (CRC) development, adverse reactions and drug resistance hinder its clinical uptake. Dysbiosis of the gut microbiota and neutrophil extracellular traps (NETs) formation are implicated in the increasing prevalence of chemoimmunotherapy resistance, which will need to be regulated to enable effective chemotherapy against CRC. To improve CRC therapy, inulin-based oral chemotherapy microspheres (ZIF-8@OXA@Inulin) are constructed. Oral inulin-based microspheres specifically adapt to the digestive system, which accurately release drugs in response to pH variations in the gastrointestinal tract. Moreover, ZIF-8@OXA@Inulin significantly enhances the intratumoral concentration and retention time of chemotherapeutic agents in an orthotopic colon tumor model, thereby further promoting pyroptosis. Additionally, ZIF-8@OXA@Inulin microspheres reshape the gut microbiota by increasing the abundance of beneficial bacterial genera (Alistipes, Lactobacillus, Enterorhabdus, and Turicibacter) and suppressing the formation of NETs induced by chemotherapy-associated side effects, ultimately facilitating T cell infiltration within the tumor microenvironment. ZIF-8@OXA@Inulin microspheres not only demonstrate excellent anti-tumor performance and antimetastatic effect but also exhibit adjuvant effects to immunotherapy agents. Collectively, the oral inulin-based microspheres (ZIF-8@OXA@Inulin) are capable of exhibiting anti-tumor activities while promoting chemotherapy and immunotherapy effects. Therefore, they show substantial application potential for CRC therapy.