Self-assembled Torkinib nanoparticles alleviate atherosclerosis via inhibition of the mTOR pathway in macrophages

Atherosclerosis (AS) remains a serious threat to human health due to its complex pathogenesis and the limited efficacy of current therapies. In this study, we developed a prodrug-based nanotherapeutic strategy for targeted inhibition of mTOR signaling in atherosclerotic plaques. The hydrophobic mTOR inhibitor Torkinib (PP242), a selective and ATP-competitive inhibitor of both mTORC1 and mTORC2, was chemically conjugated with linoleic acid (LA) to enable self-assembly into nanoparticles (LPNP). Subsequent surface PEGylation using an amphiphilic copolymer conferred excellent aqueous stability, facilitating subsequent biological evaluations. In vitro, LPNP were effectively taken up by macrophages, where they suppressed S6K phosphorylation, reduced lipid droplet accumulation, and promoted a shift from pro-inflammatory M1 to anti-inflammatory M2 polarization. Moreover, LPNP treatment enhanced cholesterol efflux from macrophages through activation of the autophagy pathway. In a mouse model of atherosclerosis, LPNP administration significantly inhibited plaque progression by reducing necrotic core area and enhancing plaque stability. Collectively, these results demonstrate that prodrug-based nanoassembly of Torkinib represents a promising and translatable strategy for the treatment of AS.