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Despite their promising prospects, the clinical translation of TEHVs remains a formidable challenge, mainly due to unpredictable host interactions post\u2010implantation. An immunomodulatory idea based on hydrogel encapsulation of nanoparticle\u2010coated heart valve scaffolds is introduced. Specifically, galactose\u2010modified human serum albumin nanoparticles (miR\u201093@HSA NPs) to deliver microRNA\u201093 mimics are utilized, which target macrophages and induce their differentiation into the anti\u2010inflammatory M2 subtype, fostering a conducive immune microenvironment. Matrix metalloproteinase (MMP)\u2010responsive hydrogel is used to encapsulate the nanoparticles, enabling targeted and sustained release. Results show that the miR\u201093@HSA NPs exhibit excellent ability to induce macrophage polarization toward the M2 phenotype. A decellularized valve modified with hydrogel reveals MMP\u2010response release of the miR\u201093@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\u2010endothelialization niche for scaffolds' constructive remodeling. With the use of cell coculture systems and transcriptome sequencing, the mechanism of immune\u2010modulating scaffold accelerating endothelialization is being elucidated. The immunomodulatory heart valve scaffold holds promising potential for clinical translation.<\/jats:p>","DOI":"10.1002\/advs.202403351","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T12:39:50Z","timestamp":1731501590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Matrix Metalloproteinase\u2010Responsive Controlled Release of Self\u2010Assembly Nanoparticles Accelerates Heart Valve Regeneration In Situ by Orchestrating Immunomodulation"],"prefix":"10.1002","volume":"12","author":[{"given":"Xing","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"},{"name":"Department of Cardiovascular Surgery Zhongnan Hospital Wuhan University  Wuhan Hubei 430071 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