Codelivery of Dual Gases with Metal‐Organic Supramolecular Cage‐Based Microenvironment‐Responsive Nanomedicine for Atherosclerosis Therapy

Abstract Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H ₂ S and in situ production of O ₂ within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)‐loaded metal‐organic cage (MOC)‐68‐doped MnO ₂ nanoparticles are developed as a microenvironment‐responsive nanodrug with the capacity for the in situ co‐delivery of H ₂ S and O ₂ to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin‐1β. In a mouse model of ApoE ^−/− genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn ²⁺ release from the acidic‐ and H ₂ O ₂ ‐ microenvironment‐responsive MnO ₂ nanoparticles. The DATS‐loaded MOC‐68‐doped MnO ₂ ‐based nanodrug holds great promise as a novel theranostic platform for AS.