Abstract

Abstract Atherosclerosis (AS) stands as a primary cause of vascular diseases worldwide, with its occurrence and progression being attributed to the interplay of multiple risk factors. Therefore, it is imperative to develop a comprehensive strategy aimed at effectively mitigating and reversing AS. Herein, a hydrogen sulfide (H 2 S) donor is incorporated into a thermal‐sensitive polymer possessing an upper critical solution temperature (UCST), which not only serves as a novel macromolecular H 2 S donor but also forms the targeted nanocarrier for delivering a near infrared II photothermal agent, achieving the gas‐photothermal therapy against AS with notable advantages. For one aspect, the multifunctional UCST nanomedicine could target atherosclerotic plaque and perform the photoacoustic imaging‐guided H 2 S‐photothermal therapy to reduce the ratio of en‐face aortic lesion areas from 17.2% to 6.5% and alleviate the inflammatory AS microenvironment. For another aspect, the inevitable hepatic accumulation of UCST nanomedicine would activate the 5'‐adenosine monophosphate (AMP)‐activated protein kinase/mammalian target of rapamycin signaling pathway, thereby enhancing lipid metabolism and reducing plasma triglyceride levels. This transformation of waste nanomedicine into the valuable asset further aids in inhibiting the progression of AS. Consequently, the multifunctional UCST nanomedicine here would mediate an effective H 2 S‐photothermal therapy to attenuate AS.