A Cathepsin‐Triggered Size‐Shrinkable Nanoparticle Enhances Fibrous Cap Penetration to Relieve Atherosclerosis

ABSTRACT In the microenvironment of atherosclerosis (AS), excessive migration of vascular smooth muscle cells led to the formation of a thick fibrous cap. This structure acted as a physical barrier and hindered efficient drug delivery to lesional macrophages. An optimal strategy for balancing long circulation with effective penetration involved the use of size‐tunable nanoformulations. Leveraging highly expressed cathepsin K (CTSK) in atherosclerotic plaques, this work reported CTSK‐responsive, size‐shrinkable nanoparticles (PDE@Mn 3 O 4 /SIM) by encapsulating trimanganese tetraoxide (Mn 3 O 4 ) and simvastatin (SIM) within CTSK‐cleavable block copolymers (PDE) to achieve controlled drug release and deep penetration within plaque sites. The resulting nanoparticles underwent rapid degradation and released smaller Mn 3 O 4 nanozymes, facilitating penetration into plaque macrophages. In vitro, the nanoparticles reduced reactive oxygen species levels and enhanced cholesterol efflux in macrophages. More importantly, they prolonged blood circulation and selectively accumulated in atherosclerotic plaques with high enzyme expression. They also markedly decreased macrophage infiltration and lipid deposition in plaques of AS mouse models. Collectively, these findings indicated that nanoparticles with CTSK‐responsive and size‐regulating properties achieved deep plaque penetration and precise macrophage targeting, serving as an effective anti‐atherosclerotic therapeutic strategy. Highlights Utilizing endogenously overexpressed cathepsin K in plaques as a biological stimulus could achieve precise and on‐demand drug release. By taking advantage of the size restriction imposed by fibrous caps, we designed microenvironment‐adaptive and size‐transformable nanoparticles for deep penetration. Co‐delivery of Mn 3 O 4 nanozyme and SIM elicited synergistic antioxidative, antiinflammatory and lipid‐modulating activities to combat atherosclerosis.