Liposomal codelivery of inflammation inhibitor and collagen protector to the plaque for effective anti-atherosclerosis

Plaque plays a central role in atherosclerosis (AS) progression, whereas inflammation and destruction of the plaque microenvironment contribute to plaque advancement. As a result, a therapy regime, which combines anti-inflammation and inhibition-degradation of plaque matrix, appears to be a promising strategy to combat AS. Herein, we report a pH-sensitive liposome co-loading with the anti-inflammatory agent (oridonin, ORD) and plaque-collagen protector (marimastat) for anti-AS therapy. ORD was first conjugated with hyaluronic acid (HA) to target the inflammation contributor, pro-inflammatory macrophages. Then, the conjugate assembled onto the MATT-loaded liposomes. The co-loaded system (∼150 nm) significantly improved pharmacokinetics over the liposomes without anchoring the conjugate and accumulated effectively in the plaque. The preparation administration allowed efficient anti-AS activities in high-fat diet (HFD)-Apoe−/− mice by decreasing the pro-inflammatory cytokine expression in the serum, lessening the lesion area, alleviating the plaque collagen degradation, promoting macrophage polarization from phenotypic M1 to M2, reducing T helper (Th) 17 cells (Th17)/T regulatory cells (Tregs) and Th1/Th2 ratio, etc. Furthermore, the serum determination in AS patients demonstrated high expression of the inflammatory cytokines, indicating our finding may offer a potential guideline for clinical practice.