Sustained release of dual p38 inhibitors via supramolecular hydrogels to enhance cardiac repair after MI/R injury.

Activation of p38 mitogen-activated protein kinase plays an important role in the progression of ventricular muscle inflammation after myocardial ischemia-reperfusion (MI/R). The inhibition of p38 activation in ischemic myocardium can reduce ventricular muscle remodeling post-MI. However, owing to the dynamic change of p38 in ischemic myocardium after MI, the clinical therapeutic effect of p38 inhibitors is insufficient. Herein, we describe the design of a hydrogelator Nap-Phe-Phe-Thr-Gly-Tyr-OH (Nap-TGY) to coassemble the p38 inhibitor SB202190 (SB), a p38 responsive supramolecular hydrogel (Gel Nap-TGY + SB) for local administration and p38 responsive release of SB to efficiently improve the inflammatory microenvironment. Under the overexpression of p38 in ischemic myocardium, Nap-TGY in the hydrogel is phosphorylated to yield hydrophilic Nap-Phe-Phe-Thr(H2PO3)-Gly-Tyr(H2PO3) (Nap-TpGYp), triggering the disassembly of the hydrogel and a responsive release of the inhibitor. Intramyocardial hydrogel injection significant reducing p38 activation, ROS levels, and inflammation while promoting macrophage reprogramming and angiogenesis. These findings demonstrate a novel therapeutic strategy for ischemic cardiomyopathy through targeted regulation of the p38 mitogen-activated protein kinase (MAPK) pathway, combined with synergistic antioxidant effects and immune reprogramming to restore tissue homeostasis.