A shear-responsive nanosystem engineered from fucoidan targets endothelial for atherosclerosis therapy.

Abstract

Hemodynamic abnormalities within atherosclerotic plaque regions, particularly localized high shear stress and endothelial dysfunction, present novel targets for intervention by drug delivery systems. In this study, we designed a polysaccharide-based carrier (HF-AF) from fucoidan, featuring a dynamic supramolecular structure. A dynamic supramolecular network was established within this carrier via dynamic supramolecular interactions between hydroxypropyl-β-cyclodextrin and adamantane-methylamine. The anti-inflammatory compound tilianin, formulated into nanocrystals (Til NCs), was then encapsulated to create a shear-responsive nanosystem (HF-AF@Til NCs). The system's primary therapeutic strategy is its response to pathological hemodynamic forces: upon encountering high shear stress at a stenosis, the supramolecular network undergoes dissociation, triggering a mechanically-gated release of the encapsulated Til NCs. This shear-triggered function is complemented by the natural P-selectin affinity of the fucoidan backbone, which facilitates the anchoring of the nanocarrier at the inflamed lesion site. This sophisticated "anchor-and-release" mechanism enables superior drug accumulation precisely at plaque sites. In ApoE^-/- atherosclerotic mice, HF-AF@Til NCs significantly reduced aortic lipid deposition and exerted potent anti-atherosclerotic effects by modulating macrophage polarization, inhibiting the NF-κ-B signaling pathway, and improving lipid profiles. In conclusion, this shear-responsive nanodelivery system, which leverages a targeting polysaccharide, effectively enhances drug accumulation and therapeutic efficacy at atherosclerotic lesions, demonstrating significant potential for the targeted therapy of atherosclerosis.