An intelligent nanoreservoir system promotes heart valve regeneration via ROS scavenging and immunomodulation.

In situ regeneration of tissue-engineered heart valves (TEHV) is a promising strategy to overcome the limitations of existing heart valve prostheses. Although, decellularized aortic valves (DAVs) are widely regarded as a scaffold in the construction of TEHV, the poor hemocompatibility and adverse immune responses make DAV scaffolds prone to thrombosis and degradation, thus hindering recellularization and in situ regeneration. Our study developed an immune-regulatory strategy involving the use of hydrogel-encapsulated nanoparticles to modify DAV scaffolds. Specifically, folic acid- and hyaluronic acid-modified mesoporous silica nanoparticles (FA-HA-MSNs@CY-09) were engineered to deliver NOD-like receptor family, pyrin domain containing 3 (NLRP3) inhibitor CY-09, thereby targeting macrophages, modulating their polarization and establishing a pro-regenerative immune microenvironment. The reactive oxygen species (ROS)-responsive hydrogel delivering FA-HA-MSNs@CY-09 enabled intelligent nanoparticle release and ROS scavenging. Results demonstrated that the hydrogel-modified DAV scaffold exhibited ROS-responsive release of FA-HA-MSNs@CY-09, which effectively induced macrophage polarization toward the pro-remodeling M2 phenotype. In vitro, the scaffold showed favorable mechanical properties, cytocompatibility, and hemocompatibility. Transcriptome sequencing elucidated the macrophage-reprogramming mechanism of the scaffold. In vivo, the scaffolds promoted significant M2 macrophage infiltration shortly after implantation, facilitating endothelial tissue formation. This resulted in enhanced endothelialization and interstitial cell infiltration under blood flow, without thrombosis or calcification. The novel heart valve overcomes various limitations of conventional heart valve prostheses and demonstrates considerable promise for clinical translation, particularly as an immunomodulatory biomaterial strategy.