Inflammation-Responsive Baicalin-Delivering Glycocalyx-Mimetic Hydrogel-Functionalized Bioprosthetic Valve for Antithrombosis and Immunomodulation.

Valvular heart disease (VHD), a prevalent age-associated condition associated with high mortality, is primarily treated by prosthetic valve replacement. Bioprosthetic heart valves (BHVs) are increasingly preferred in clinical practice owing to their favorable hemodynamic performance and compatibility with transcatheter delivery. However, current glutaraldehyde crosslinking fails to confer antithrombotic, antioxidant, and immunomodulatory properties, leaving BHVs prone to thrombosis, oxidative stress, inflammation, and calcification, all of which accelerate structural valve deterioration (SVD) and shorten their lifespan. Herein, an inflammation-responsive, glycocalyx-mimetic hydrogel-functionalized BHV (BA@ALG-PP) was constructed using mussel-inspired catechol chemistry, which integrated a vascular glycocalyx-like layer with baicalin-loaded, reactive oxygen species (ROS)-responsive nanoparticles. With the introduction of a biocompatible glycocalyx-mimetic layer on the xenogeneic collagenous matrix, BA@ALG-PP exhibited improved antithrombotic and endothelialization performance, which was further confirmed in vivo by the rabbit intravascular implantation experiment. Moreover, the ROS-responsive nanoparticles effectively scavenged oxidative species and enabled stimulus-responsive on-demand release of anti-inflammatory molecule baicalin, thereby modulating local inflammatory responses. Transcriptional analysis of macrophages indicated that BA@ALG-PP regulated the expression of key inflammatory-related genes (Tnfaip3, Hmox1, Stat1, and Saa3) as well as suppressed pro-inflammatory signaling pathways, including NF-κB, MAPK, and JAK-STAT. Furthermore, BA@ALG-PP demonstrated improved anti-calcification property in the subcutaneous implantation experiments in rats. Collectively, this multifunctional strategy endows BHVs with synergistic antithrombotic, antioxidant, immunomodulatory, and anti-calcification capabilities, thereby offering a potential strategy for improving BHV performance that warrants further investigation in large animal models and potentially mitigating factors contributing to SVD. STATEMENT OF SIGNIFICANCE: Glutaraldehyde-crosslinked bioprosthetic heart valves (BHVs) suffer from structural valve deterioration driven by thrombosis, oxidative stress, and chronic inflammation, yet current surface engineering strategies remain functionally limited. This study reports an inflammatory-responsive glycocalyx-mimetic hydrogel functionalized BHV (BA@ALG-PP) engineered via mussel-inspired catechol chemistry. The system integrates non-glutaraldehyde crosslinking, ROS-responsive baicalin release, and endothelial glycocalyx mimicry into a multifunctional platform. BA@ALG-PP demonstrates enhanced antithrombotic performance, accelerated endothelialization, effective ROS scavenging, and macrophage polarization from M1 to M2 phenotype through NF-κB, MAPK, and JAK-STAT pathway modulation. Furthermore, it significantly reduces calcification in vivo. This work establishes a comprehensive strategy for BHV crosslinking and surface engineering, offering a clinically translatable strategy to prolong BHV durability and improve patient outcomes.