Esterase-Responsive Self-Assembled Torkinib Prodrug Nanoparticles Alleviate Atherosclerosis via Macrophage mTOR Inhibition

Atherosclerosis remains a major threat to human health due to unresolved plaque inflammation and macrophage dysfunction. Although stimuli-responsive nanocarriers (e.g., pH- or ROS-sensitive systems) have been exploited for targeted Drug Delivery, they suffer from modest signal gradients, spatial heterogeneity, or unpredictable release in atherosclerotic lesions. Herein, we report an esterase-responsive, carrier-free self-assembling prodrug nano-platform (LPNP) that exploits the unique pathological microenvironment of atherosclerotic plaques for targeted mTOR inhibition in lesional Macrophages. The dual mTORC1/2 inhibitor Torkinib (PP242) was covalently conjugated to linoleic acid (LA) via a labile ester bond, enabling spontaneous nanoparticle formation without exogenous carriers. This ester bond remains stable during systemic circulation but is efficiently cleaved by intracellular esterases-highly active in macrophage-derived foam cells-enabling lesion-specific drug release. In vitro, LPNPs were readily internalized by Macrophages, where they suppressed S6K phosphorylation, activated Autophagy, reduced ROS levels, and upregulated ABCA1/ABCG1-mediated Cholesterol efflux, thereby reducing lipid droplet accumulation and promoting M1-to-M2 repolarization. In an ApoE-/- mouse model, LPNP administration significantly reduced plaque burden, increased Collagen deposition, and enhanced plaque stability without altering systemic lipid profiles or causing overt toxicity. Collectively, this esterase-responsive prodrug strategy couples carrier-free self-assembly with macrophage-associated intracellular activation, providing a promising approach to enhance lesional macrophage mTOR inhibition for Atherosclerosis treatment.