Matrix Metalloproteinase‐Responsive Controlled Release of Self‐Assembly Nanoparticles Accelerates Heart Valve Regeneration In Situ by Orchestrating Immunomodulation

Abstract In situ tissue engineering heart valves (TEHVs) are the most promising way to overcome the defects of existing valve prostheses. Despite their promising prospects, the clinical translation of TEHVs remains a formidable challenge, mainly due to unpredictable host interactions post‐implantation. An immunomodulatory idea based on hydrogel encapsulation of nanoparticle‐coated heart valve scaffolds is introduced. Specifically, galactose‐modified human serum albumin nanoparticles (miR‐93@HSA NPs) to deliver microRNA‐93 mimics are utilized, which target macrophages and induce their differentiation into the anti‐inflammatory M2 subtype, fostering a conducive immune microenvironment. Matrix metalloproteinase (MMP)‐responsive hydrogel is used to encapsulate the nanoparticles, enabling targeted and sustained release. Results show that the miR‐93@HSA NPs exhibit excellent ability to induce macrophage polarization toward the M2 phenotype. A decellularized valve modified with hydrogel reveals MMP‐response release of the miR‐93@HSA NPs. In vitro, the immunomodulatory heart valve possesses good endocytocompatibility and effectively reprograms macrophages when cocultured with HUVECs or RAW264.7 macrophages. In vivo, this valve scaffold promises to mitigate early inflammatory damage and provide a pro‐endothelialization niche for scaffolds' constructive remodeling. With the use of cell coculture systems and transcriptome sequencing, the mechanism of immune‐modulating scaffold accelerating endothelialization is being elucidated. The immunomodulatory heart valve scaffold holds promising potential for clinical translation.