Injectable alginate composite hydrogel with spatiotemporal codelivery of pro-angiogenic and anti-fibrotic agents for synergistic myocardial repair.

Myocardial infarction (MI), a leading cause of heart failure, involves dynamic pathological progression from acute ischemia to maladaptive fibrosis. To address this complexity, we engineered an injectable alginate composite hydrogel enabling spatiotemporal codelivery of dual therapeutics targeting distinct MI phases. The system incorporates: (i) UCL-TRO-1938, a newly identified PI3Kα activator promoting angiogenesis via PI3K/Akt signaling, released immediately during the acute injury phase; and (ii) engineered mesoporous silica nanoparticles encapsulating bone morphogenetic protein-9 (BMP-9); these nanoparticles feature an epigallocatechin gallate/zinc ion complex coating enabling pH-responsive payload release specifically within acidic infarct microenvironments. This design aims to align the release of UCL-TRO-1938 with the early demands of angiogenesis and delay BMP-9 release to coincide with the later phase of fibrosis progression. Comparative studies in murine myocardial infarction models showed that this dual-delivery platform resulted in improved outcomes compared with single-agent therapies. Intramyocardial administration significantly reduced apoptosis, enhanced angiogenesis, attenuated fibrosis, and improved cardiac function relative to controls. By synchronizing material properties with stage-specific biological responses, this temporally programmed strategy, which aligns with the pathological progression of MI, achieves enhanced functional recovery compared to conventional monotherapies, providing a clinically viable approach for myocardial repair.