Zhu_2026_ACS.Appl.Mater.Interfaces__

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.