J Control Release. 2026 Mar 14:114821. doi: 10.1016/j.jconrel.2026.114821. Online ahead of print.
ABSTRACT
Atherosclerotic plaque rupture, driven by a vicious pathological cycle between endothelial-to-mesenchymal transition (EndMT) and chronic inflammation, represents a major therapeutic challenge in cardiovascular disease. Current clinical strategies, including statins and antiplatelet agents, fail to disrupt the EndMT-inflammation axis, while conventional TGF-β pathway inhibitors-critical for EndMT regulation-exhibit narrow therapeutic windows and systemic toxicity owing to the pleiotropic nature of TGF-β signaling. Here, we reported VRBPC, a VCAM-1-targeting, reactive oxygen species (ROS)-responsive baicalin-peptide conjugate that undergoes in situ self-assembly within atherosclerotic plaques to form a "molecular latch" that breaks the EndMT-inflammation loop. Upon VCAM-1-mediated endocytosis into activated endothelial cells, VRBPC responds to elevated ROS levels in the plaque microenvironment, triggering localized self-assembly that enhances baicalin retention and promotes its competitive binding to HSP90-a critical chaperone for TGF-β receptor stabilization. This mechanism inhibits Smad2/3 phosphorylation, reverses EndMT, and simultaneously suppresses inflammatory responses in macrophages. In vitro, VRBPC effectively restored endothelial phenotype, reduced aberrant migration, and diminished foam cell formation alongside pro-inflammatory cytokine secretion. In ApoE-/- mice, VRBPC demonstrated enhanced aortic accumulation, achieving reduced plaque area and increased collagen content-hallmarks of stabilized plaques-with excellent biocompatibility and no detectable systemic toxicity. These findings establish in situ self-assembling peptide-drug conjugates as agents that break the vicious pathological loops in atherosclerosis via microenvironment-responsiveness, offering a new paradigm for precision therapy of atherosclerosis and inflammatory vascular diseases.
PMID:41839263 | DOI:10.1016/j.jconrel.2026.114821