CCL17-neutralizing and esterase-responsive core-shell microgels for endogenous Tregs recruitment and functional enhancement in myocardial infarction.

Abstract

Myocardial infarction (MI) disrupts immune homeostasis by impairing the recruitment and suppressive function of regulatory T cells (Tregs), which are hard to restore to date. In this study, a dual-functional platform based on core-shell microgels (Ab/HAPA C-S MGs) was developed to enhance Tregs homing and function within the post-infarct environment. The surface-modified C-C motif chemokine ligand 17 (CCL17) antibody neutralized excess CCL17, thereby enabling targeted Tregs recruitment. Propionic acid (PA) was released via hydrolytic cleavage of an encapsulated prodrug precursor (HAPA) within the core to promote Tregs immunosuppressive activity through fatty acid oxidation. The platform ensured localized retention and release of PA, addressing the pharmacokinetic limitations characteristic of short-chain fatty acid (SCFAs). The Ab/HAPA@C-S MGs enhanced Tregs recruitment by 4.2-fold through CCL17 neutralization, while enzymatically released PA boosted Tregs immunosuppression with 1.8-fold higher Foxp3 expression <i>in vitro</i>. In MI models, treatment with Ab/HAPA@C-S MGs promoted a 2.4-fold increase in Tregs infiltration while reducing Th17 cells in infarcted region, ultimately improving cardiac functions and attenuating myocardial fibrosis. These findings show potential of the SCFA-based C-S MGs system on regulating the immunomodulation and cardiac tissue repair.