Chiral D-peptide composite hydrogels enable sustained RepSox delivery and antifibrotic remodeling after myocardial...

Persistent oxidative stress and profibrotic signaling after myocardial infarction (MI) contribute to adverse ventricular remodeling. Although peptide hydrogels show potential for MI treatment, conventional L-peptides are susceptible to rapid enzymatic degradation, which can lead to premature drug release and limited therapeutic durability. Here, we developed a chiral composite hydrogel (D Gel@RepSox) by combining self-assembling D-enantiomeric antioxidant peptides with RepSox-loaded nanoparticles. Compared with the corresponding L-peptide hydrogel, the D-peptide system showed greater proteolytic resistance, prolonged retention, and more sustained drug release. The peptide hydrogel also retained intrinsic bioactivity and contribute to regulation of the local microenvironment after MI. Accordingly, D Gel@RepSox exerted therapeutic effects during both the inflammatory and remodeling phases. At day 28 after MI, treatment with D Gel@RepSox was associated with improved cardiac function, a 34.0% reduction in collagen volume fraction, and increases in ejection fraction (EF) and fractional shortening (FS) of 33.5% and 27.4%, respectively. Transcriptomic, gene, and protein level analyses further suggested that these effects may be associated, at least in part, with suppression of profibrotic signaling, including the TGF-β/Smad3 pathway. Together, these findings support peptide chirality engineering as a strategy to improve hydrogel stability and enable sustained antifibrotic drug delivery for myocardial repair.