Macrophage‐targeted cerium‐tannic acid metal‐polyphenol framework nanoenzyme promotes in situ heart valves regeneration through adaptive immunomodulation

Abstract Constructing in situ tissue engineered heart valves based on xenogeneic decellularized heart valves (DHVs) is a promising strategy for heart valve regeneration. However, the inflammation triggered by foreign body responses results in maladaptive matrix remodeling and compromised mechanical support. Given the critical role of macrophages (M ø s) in regulating several homeostasis to relieve xenogeneic rejection and promote tissue regeneration, folic acid modified cerium ions‐tannic acid metal‐polyphenol framework nanoparticles (FCT NPs) have been synthesized via a green coordination method and then loaded onto thiolated DHVs to reprogram macrophage phenotype. FCT NPs, with multiple enzyme‐mimicking activity, biodegradability and biocompatibility, moderately scavenge various reactive oxygen species in M1 M ø s, reprogramming them to increase the M2 phenotype. This reduces inflammatory factors levels and promotes secretion of anti‐inflammatory and pro‐regenerative cytokines, enabling elimination of inflammation and promotion of adaptive matrix remodeling. In vitro studies show that FCT‐loaded DHVs (FCT@DHVs) exhibit excellent immunomodulatory capability, mechanical properties, hemocompatibility, and cytocompatibility. Rat implantation models reveal that FCT@DHVs achieve re‐endothelialization and adaptive matrix remodeling via immunomodulation. They also exhibit excellent hemodynamics, hemocompatibility, histocompatibility, anti‐calcification and mechanical support. Notably, M2 M ø s numbers decrease with scaffold degradation, indicating self‐adaptive immunomodulation. This strategy offers a promising approach for in situ heart valve regeneration based on xenogeneic DHVs.