A pH-responsive GelMA-KerMA hydrogel delivering luteolin-loaded PLGA nanoparticles promotes myocardial repair via Akt/Bad signaling and multitarget regulation

Myocardial infarction (MI) triggers cardiomyocyte apoptosis, oxidative stress imbalance, ventricular fibrosis, and impaired angiogenesis. Luteolin, a natural flavonoid compound, possesses antioxidant, anti-apoptotic, and cardioprotective properties, making it a promising candidate for MI treatment. However, its poor water solubility, low bioavailability, and chemical instability severely hinder its clinical translation. To address these limitations, we developed a photo-crosslinked composite hydrogel delivery system using gelatin methacryloyl and keratin methacryloyl (GelMA-KerMA). Luteolin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were uniformly dispersed within a three-dimensional gel network to achieve pH-triggered local drug delivery. The covalent GelMA-KerMA network retained structural integrity under both pH conditions. In the weakly acidic infarct microenvironment, acid-catalyzed hydrolysis of PLGA ester bonds was the primary driver of accelerated luteolin release, whereas the network mainly acted as a sustained-retarding reservoir. The incorporation of KerMA endowed the patch with enhanced mechanical stability and cytocompatibility, enabling better mechanical matching with the infarcted myocardium. The composite hydrogel promotes myocardial repair and functional recovery through the coordinated regulation of the rapid Akt/Bad phosphorylation cascade. It also sustains MAPK/Rap1-dependent transcriptional reprogramming. It inhibits mitochondrial apoptosis, scavenges reactive oxygen species (ROS), suppresses fibroblast activation, and promotes neovascularization. This study presents a protein-based delivery platform that integrates tailored physicochemical and mechanical properties with multi-pathway myocardial repair capabilities, offering a biomaterial strategy for minimally invasive local drug delivery in ischemic MI.