Chiral D-peptide hydrogel (D Gel@RepSox) improves cardiac function and cuts fibrosis 34% after myocardial infarction

Adverse ventricular remodeling following myocardial infarction (MI) is a major contributor to heart failure, driven by persistent oxidative stress and profibrotic signaling. Current therapeutic strategies often struggle with sustained drug delivery and the harsh post-MI microenvironment. While peptide hydrogels offer promise for localized treatment, conventional L-peptides are rapidly degraded by enzymes, leading to premature drug release and limited therapeutic durability. This study addresses this gap by leveraging D-enantiomeric peptides to create a more stable and effective delivery system.

Researchers engineered a chiral composite hydrogel, D Gel@RepSox, by combining self-assembling D-enantiomeric antioxidant peptides with RepSox-loaded nanoparticles. They compared its proteolytic resistance, retention, and drug release profile against a corresponding L-peptide hydrogel. The therapeutic efficacy of D Gel@RepSox was then evaluated in a myocardial infarction (MI) model, assessing its impact during both inflammatory and remodeling phases. Primary endpoints included cardiac function (ejection fraction, fractional shortening), collagen volume fraction, and molecular analyses using transcriptomics, gene expression, and protein level analyses at day 28 post-MI.

The D Gel@RepSox system demonstrated superior proteolytic resistance, prolonged retention, and more sustained drug release compared to its L-peptide counterpart. It also maintained intrinsic bioactivity, contributing to local microenvironment regulation post-MI. Therapeutic effects were observed during both the inflammatory and remodeling phases. At day 28 after MI, treatment with D Gel@RepSox significantly improved cardiac function. Specifically:

Treatment with D Gel@RepSox at day 28 post-MI led to a 34.0% reduction in collagen volume fraction, alongside significant increases in ejection fraction (EF) by 33.5% and fractional shortening (FS) by 27.4%. These beneficial effects were further supported by transcriptomic, gene, and protein level analyses, suggesting an association with the suppression of profibrotic signaling, particularly the TGF-β/Smad3 pathway.