Myocardia‐Injected Synergistically Anti‐Apoptotic and Anti‐Inflammatory Poly(amino acid) Hydrogel Relieves Ischemia‐Reperfusion Injury

Reperfusion therapy is the most effective treatment for acute myocardial infarction, but its efficacy is frequently limited by ischemia-reperfusion injury (IRI). While antioxidant and anti-inflammatory therapies have shown significant potential in alleviating IRI, these strategies have not yielded satisfactory clinical outcomes. For that, a thermo-sensitive myocardial-injectable poly(amino acid) hydrogel of methoxy poly(ethylene glycol)₄₅-poly(L-methionine₂₀-co-L-alanine₁₀) (mPEG₄₅-P(Met₂₀-co-Ala₁₀), PMA) loaded with FTY720 (PMA/FTY720) is developed to address IRI through synergistic anti-apoptotic and anti-inflammatory effects. Upon injection into the ischemic myocardium, the PMA aqueous solution undergoes a sol-to-gel 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-inflammatory M1 macrophage polarization toward anti-inflammatory 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-based 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-apoptosis and anti-inflammation actions, offering valuable clinical potential for treating myocardial IRI.