Intelligent response micelles with high andrographolide loading for the effective treatment of atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment.