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

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.