Functional ECM Hydrogel for Targeted Delivery of bFGF and Angiopoietin-1 Mimetic Peptide Enhances Neurovascular Regeneration in Ischemic Stroke

Ischemic stroke (IS) remains a major cause of global disability and mortality. Currently, neuroprotection, angiogenesis, and repair of injured blood brain barrier (BBB) are common regenerative therapy strategies for IS. The primary challenge remains how to integrate these processes into a synergistic tissue repair program in response to microenvironmental cues. In the present study, a functional ECM hydrogel was constructed by combining with specific ECM-binding bFGF (EBP-bFGF) for neuroprotection and chemically modifying with a matrix metalloproteinase-2 (MMP-2)-cleavable motif to control the release of angiopoietin-1 mimetic peptide (AMP), thereby promoting angiogenesis and BBB repair. After verification of the biological activity in vitro, the EBP-bFGF/ECM/TIMP-AMP hydrogel was transplanted into ischemic brain following IS. The findings indicated that the application of the innovative EBP-bFGF/ECM/TIMP-AMP hydrogel facilitated the preservation of neuronal integrity and conferred potent neuroprotection. Additionally, the therapeutic intervention significantly stimulated angiogenesis and achieved stabilization of the blood brain barrier through inhibition of MMP-2 overactivity, thereby diminishing vascular permeability. Collectively, these findings establish the targeted, stimulus-responsive co-delivery of bFGF and TIMP-AMP as a promising regenerative strategy, which orchestrates neuroprotection, angiogenesis, and BBB stabilization to synergistically promote repair and recovery after ischemic stroke.