Injectable pH-responsive hydrogel with anti-inflammatory, pro-angiogenic, and anti-fibrotic multifunctional effects for myocardial infarction regeneration

Myocardial infarction (MI) leads to adverse cardiac remodeling and heart failure, necessitating innovative therapeutic strategies. This study developed an injectable, pH-responsive methacrylated carboxymethyl chitosan (M-CMCS) hydrogel loaded with recombinant tissue factor pathway inhibitor 2 (rTFPI2) and vascular endothelial growth factor (VEGF)-encapsulated mesoporous silica nanoparticles (MSN) for stage-specific MI treatment. The hydrogel exhibited excellent biocompatibility, mechanical properties, and controlled drug release, with rapid VEGF (73.24%) and rTFPI2 (74.11%) release under acidic conditions (pH 5.0). In vitro, the hydrogel scavenged reactive oxygen species, reduced apoptosis in H9C2 cardiomyocytes, and modulated macrophage polarization from pro-inflammatory M1 to reparative M2 phenotypes, suppressing IL-6 and TNF-α secretion. It also enhanced cardiac microvascular endothelial cell (CMECs) proliferation, migration, and angiogenesis while inhibiting cardiac fibroblast activation. In a mice MI model, the hydrogel significantly reduced infarct size, improved cardiac function (ejection fraction and fractional shortening), and attenuated fibrosis. Immunohistochemistry confirmed enhanced CD31+ vascular density, reduced MMP2/MMP9 expression, and promoted macrophage polarization toward the M2 phenotype. These results demonstrate the hydrogel's comprehensive therapeutic effects through anti-inflammatory, pro-angiogenic, and anti-fibrotic mechanisms, offering a promising multi-target approach for MI therapy. The study highlights the potential of smart hydrogels to dynamically modulate cardiac repair processes, paving the way for clinical translation. • Injectable pH-responsive hydrogel enables stage-specific therapy for myocardial infarction. • Dual-drug delivery system combines anti-inflammatory and pro-angiogenic effects. • Significantly improves cardiac function and reduces fibrosis in MI model • Smart material responds to pathological microenvironment for controlled release. • Demonstrates excellent biocompatibility and therapeutic potential