Pyroptosis is a form of programmed cell death (PCD) that bolsters local and systemic inflammatory responses, which is closely associated with atherosclerosis (AS) progression and plaque vulnerability. Although current treatments have achieved satisfactory progress in suppressing pyroptosis, there are significant challenges remaining in effectively alleviating plaque burden due to issues including poor site specificity, extensive systemic distribution, and undesirable side effects. Herein, intelligent living cell-based drug delivery systems (LC-DDSs) targeting AS intervention with distinct functions was designed by loading disulfiramand (DSF) and the phase-transition perfluorohexane (PFH) onto the bovine serum albumin (BSA)-modified Co2Mo3O8 nanosheets, followed by phagocytosis into macrophages to construct PDCos@Ms. Upon ultrasonic irradiation, these nanoengineered PDCos@Ms can generate microbubbles, enabling controlled release of their therapeutic payloads. This mechanism effectively ameliorates AS progression and enhances plaque stability by suppressing programmed cell pyroptosis and promoting an anti-inflammatory macrophage phenotype through scavenging reactive oxygen species, reducing the expression of pyroptosis-associated proteins and diminishing the leakage of inflammatory factors. Meanwhile, the PFH integrated within the system facilitate real-time ultrasonic imaging, allowing for image-guided atherosclerotic therapy. The proposed biomimetic therapeutic strategy holds significant potential for efficient plaque diminishing and provides a distinct paradigm of LC-DDSs for AS management.
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