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While antioxidant and anti\u2010inflammatory therapies have shown significant potential in alleviating IRI, these strategies have not yielded satisfactory clinical outcomes. For that, a thermo\u2010sensitive myocardial\u2010injectable poly(amino acid) hydrogel of methoxy poly(ethylene glycol)<jats:sub>45<\/jats:sub>\u2010poly(L\u2010methionine<jats:sub>20<\/jats:sub>\u2010<jats:italic>co<\/jats:italic>\u2010L\u2010alanine<jats:sub>10<\/jats:sub>) (mPEG<jats:sub>45<\/jats:sub>\u2010P(Met<jats:sub>20<\/jats:sub>\u2010<jats:italic>co<\/jats:italic>\u2010Ala<jats:sub>10<\/jats:sub>), PMA) loaded with FTY720 (PMA\/FTY720) is developed to address IRI through synergistic anti\u2010apoptotic and anti\u2010inflammatory effects. Upon injection into the ischemic myocardium, the PMA aqueous solution undergoes a sol\u2010to\u2010gel phase transition and gradually degrades in response to reactive oxygen species (ROS), releasing FTY720 on demand. PMA acts synergistically with FTY720 to inhibit cardiomyocyte apoptosis and modulate pro\u2010inflammatory M1 macrophage polarization toward anti\u2010inflammatory M2 macrophages by clearing ROS, thereby mitigating the inflammatory response and promoting vascular regeneration. In a rat IRI model, PMA\/FTY720 reduces the apoptotic cell ratio by 81.8%, increases vascular density by 34.0%, and enhances left ventricular ejection fraction (LVEF) by 12.8%. In a rabbit IRI model, the gel\u2010based sustained release of FTY720 enhanced LVEF by an additional 7.2% compared to individual treatment. In summary, the engineered PMA hydrogel effectively alleviates IRI through synergistic anti\u2010apoptosis and anti\u2010inflammation actions, offering valuable clinical potential for treating myocardial IRI.<\/jats:p>","DOI":"10.1002\/adma.202420171","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T04:05:13Z","timestamp":1738728313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Myocardia\u2010Injected Synergistically Anti\u2010Apoptotic and Anti\u2010Inflammatory Poly(amino acid) Hydrogel Relieves Ischemia\u2010Reperfusion Injury"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0343-5208","authenticated-orcid":false,"given":"Qiang","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Cardiology The Second Hospital of Jilin University  4026 Yatai Street Changchun 130041 P. R. 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