This study demonstrates that an adhesive implant–tissue interface can prevent fibrous capsule formation in diverse animal models, including rats, mice, humanized mice, and pigs. The adhesive interface reduces the infiltration of inflammatory cells into the implant–tissue interface, leading to decreased collagen deposition and fibrous capsule formation. Histological analysis shows no observable fibrous capsule formation on organs such as the abdominal wall, colon, stomach, lung, and heart over 12 weeks. In vitro assays, including protein adsorption, multiplex Luminex, quantitative PCR, immunofluorescence, and RNA sequencing, validate the hypothesis. The adhesive interface also enables long-term bidirectional electrical communication in a rat model. Foreign body reactions to implants are a major challenge for long-term functionality, as fibrous capsules can block mechanical, electrical, chemical, and optical communications. Various approaches have been developed to mitigate fibrous capsule formation, but challenges remain. The adhesive interface provides mechanical integration and prevents fibrous capsule formation by reducing inflammatory cell infiltration. The study shows that the adhesive interface prevents fibrous capsule formation in diverse organs and models, and that the interface is required to prevent fibrous capsule formation. The adhesive interface also shows comparable adhesion performance to a chitosan-based interface. Histological analysis shows no fibrous capsule formation on day 14 post-implantation. The study also shows that the adhesive interface reduces the formation of fibrous capsules in diverse animal models, including C57BL/6 mice, humanized mice, and pigs. The adhesive interface enables long-term in vivo electrophysiological recording and stimulation in a rat model. The study provides a promising strategy for long-term anti-fibrotic implant–tissue interfaces.This study demonstrates that an adhesive implant–tissue interface can prevent fibrous capsule formation in diverse animal models, including rats, mice, humanized mice, and pigs. The adhesive interface reduces the infiltration of inflammatory cells into the implant–tissue interface, leading to decreased collagen deposition and fibrous capsule formation. Histological analysis shows no observable fibrous capsule formation on organs such as the abdominal wall, colon, stomach, lung, and heart over 12 weeks. In vitro assays, including protein adsorption, multiplex Luminex, quantitative PCR, immunofluorescence, and RNA sequencing, validate the hypothesis. The adhesive interface also enables long-term bidirectional electrical communication in a rat model. Foreign body reactions to implants are a major challenge for long-term functionality, as fibrous capsules can block mechanical, electrical, chemical, and optical communications. Various approaches have been developed to mitigate fibrous capsule formation, but challenges remain. The adhesive interface provides mechanical integration and prevents fibrous capsule formation by reducing inflammatory cell infiltration. The study shows that the adhesive interface prevents fibrous capsule formation in diverse organs and models, and that the interface is required to prevent fibrous capsule formation. The adhesive interface also shows comparable adhesion performance to a chitosan-based interface. Histological analysis shows no fibrous capsule formation on day 14 post-implantation. The study also shows that the adhesive interface reduces the formation of fibrous capsules in diverse animal models, including C57BL/6 mice, humanized mice, and pigs. The adhesive interface enables long-term in vivo electrophysiological recording and stimulation in a rat model. The study provides a promising strategy for long-term anti-fibrotic implant–tissue interfaces.