Constructing Immunomodulator Biosynthesis Factory in Grafting‐From DNA Hydrogel for Heart Valve Regeneration

Abstract The development of heart valve prostheses with regenerative capabilities offers significant potential to overcome the limitations of existing commercial artificial valves in clinical practice. Immune modulation plays a crucial role in heart valve regeneration by reversing the coagulation and inflammatory microenvironment, thereby facilitating recellularization. In this study, a biosynthesis factory is constructed on decellularized heart valves (DHVs) to continuously convert the abundant heme in the blood into immunomodulators, supporting long‐term immune modulation and tissue regeneration. This biosynthesis factory is achieved through a grafting from DNA hydrogel, utilizing tailored rolling circle amplification (RCA) on DHVs. Anti‐coagulation NU172 aptamers are incorporated into the DNA hydrogel to recruit heme from the bloodstream, while heme oxygenase 1 (HO‐1) is encapsulated to simultaneously convert heme into biliverdin. This system ensures the sustained production of biliverdin, facilitating anti‐inflammatory immune modulation and reactive oxygen species (ROS) scavenging, thus creating a regenerative immune microenvironment. Additionally, the DNA coating is further crosslinked with zwitterionic polymers, which protect the functional DNA layer and provide anti‐calcification and anti‐adhesion properties. This comprehensive design promotes full endothelial cell coverage and significant extracellular matrix remodeling within one‐month post‐implantation.