Metabolic-switch macrophage cyborgs reverse atherosclerosis by photoacoustic-directed on-demand phenotype delivery

Abstract

Pathological macrophage activation orchestrates atherosclerotic plaque progression through sustained inflammation, necrotic core expansion, and plaque destabilization, a process recalcitrant to current targeted therapies. We address this fundamental challenge by engineering a living macrophage-based theranostic cyborg (MφMB-Au) that integrates precision plaque homing with spatiotemporally controlled immunomodulation. This platform exploits the innate inflammatory tropism of functionalized macrophages to co-deliver gold nano-regulator (AuNPs) and real-time tracer microbubbles (MBs). The AuNPs function dually as high-sensitivity photoacoustic imaging agents, enabling deep-tissue quantification of plaque burden, and potent metabolic switches reprogramming macrophage polarization via lipid and energy metabolism pathways. Concurrently, MBs facilitate real-time ultrasonographic tracking with micron-scale spatial resolution. In vivo studies demonstrate sustained plaque-specific accumulation of MφMB-Au, permitting longitudinal dual-modal ultrasound/photoacoustic imaging for over 24 hours. Ultrasound-triggered payload release induced a 5.3-fold increment of M2-repolarization, driving significant plaque regression. Critically, this approach restored efferocytosis capacity and collagen deposition while evading off-target toxicity. As the first cellular cyborg platform unifying longitudinal multimodal imaging, stimuli-responsive cargo deployment, and metabolic reprogramming, this work establishes a paradigm-shifting theranostic strategy to reverse the core pathophysiology of atherosclerosis.