Targeted inhibition of M2 macrophages polarization via a PDC attenuates chronic pancreatitis through the PPARα pathway.

This study examines the pivotal role of M2-type macrophages in chronic pancreatitis (CP) and the existing challenges in targeted intervention. A peptide-drug conjugate (PDC) was developed for this investigation by linking the S100A9 inhibitor Tasquinimod to a peptide that selectively targets M2 macrophages. In experimental models, this conjugate demonstrated a marked capacity to alleviate pancreatic injury, inflammation, and fibrotic progression. Compared to the free drug, it showed enhanced targeting, greater efficacy, and a reduced toxicity profile without causing significant damage to vital organs. Mechanistic analysis indicated that its effects are mediated through the activation of the peroxisome proliferator-activated receptor α (PPARα) signaling pathway, leading to suppressed phosphorylation of the NF-κB p65 subunit and c-Jun, which in turn inhibits M2 macrophage polarization. These results uncover a functional mechanism and provide a foundation for developing targeted immunomodulatory therapies against CP.