A bioelectronic system called iMASSAGE was developed to produce therapeutic extracellular vesicles (EVs) in situ for gut microbiota modulation. The system uses wireless stimulation to mechanically activate macrophages embedded in a hydrogel, significantly increasing EV production. This approach overcomes the limitations of traditional methods, such as allogeneic fecal microbiota transplantation (FMT), which have issues with safety and sustainability. The iMASSAGE system, which is implanted in the mesentery, allows for on-demand EV production, which can be remotely controlled and is more effective than natural EV production. The system was tested in a mouse model of inflammatory bowel disease (IBD), where it showed significant improvements in gut microbiota balance and reduced inflammation. The EVs produced by the system were found to be effective in modulating the gut microbiome, increasing the abundance of beneficial bacteria and reducing harmful ones. The system also demonstrated the ability to produce a large number of EVs, with a production rate more than 2000% higher than natural levels. The iMASSAGE system is a promising platform for the treatment of various diseases, including IBD, by enabling the controlled production of EVs that can modulate the gut microbiome. The system's wireless and programmable nature allows for precise control over EV production, making it a valuable tool for future therapeutic applications. The study highlights the potential of EVs as a novel therapeutic approach for modulating the gut microbiome and treating diseases such as IBD. The iMASSAGE system represents a significant advancement in the field of bioelectronic medicine, offering a new method for the in situ production of EVs for therapeutic use.A bioelectronic system called iMASSAGE was developed to produce therapeutic extracellular vesicles (EVs) in situ for gut microbiota modulation. The system uses wireless stimulation to mechanically activate macrophages embedded in a hydrogel, significantly increasing EV production. This approach overcomes the limitations of traditional methods, such as allogeneic fecal microbiota transplantation (FMT), which have issues with safety and sustainability. The iMASSAGE system, which is implanted in the mesentery, allows for on-demand EV production, which can be remotely controlled and is more effective than natural EV production. The system was tested in a mouse model of inflammatory bowel disease (IBD), where it showed significant improvements in gut microbiota balance and reduced inflammation. The EVs produced by the system were found to be effective in modulating the gut microbiome, increasing the abundance of beneficial bacteria and reducing harmful ones. The system also demonstrated the ability to produce a large number of EVs, with a production rate more than 2000% higher than natural levels. The iMASSAGE system is a promising platform for the treatment of various diseases, including IBD, by enabling the controlled production of EVs that can modulate the gut microbiome. The system's wireless and programmable nature allows for precise control over EV production, making it a valuable tool for future therapeutic applications. The study highlights the potential of EVs as a novel therapeutic approach for modulating the gut microbiome and treating diseases such as IBD. The iMASSAGE system represents a significant advancement in the field of bioelectronic medicine, offering a new method for the in situ production of EVs for therapeutic use.