BACKGROUND: Porphyrin-lipid nanoparticles (Por-NPs) have unrealized potential for atherosclerosis. Por-NPs incorporate porphyrin-lipid which permits fluorescence imaging and chelates Copper-64 (Cu) for positron emission tomography (PET) imaging. Their outer shell contains a short peptide 'R4F' that enables macrophage targeting and therapeutic effects. Accordingly, this study investigates the simultaneous diagnostic and therapeutic properties of Por-NPs in atherosclerosis. RESULTS: , Por-NPs were found to be internalized by immortalised bone marrow-derived macrophages (iBMDMs), visualized via fluorescence microscopy and flow cytometry. Por-NPs also increased cholesterol efflux from [H]-cholesterol-loaded iBMDMs, (49 %,  < 0.05). Incubation of iBMDMs with Por-NPs reduced mRNA levels of inflammatory mediators (88 %), (54 %) (75 %) and (92 %), and protein secretion of IL-1β (69 %), CCL5 (82 %) and CCL17 (94 %),  < 0.05. Por-NPs suppressed inflammasome components (69 %) and (36 %),  < 0.05. Studies using siRNA deletion of SR-B1 and methyl-β-cyclodextrin, revealed the anti-inflammatory properties of Por-NPs were independent of SR-B1 and cholesterol efflux. However, Por-NPs suppressed activation of inflammatory transcription factor NF-κB (53 %,  < 0.05). , in mice, serial non-invasive PET imaging showed Cu-labelled Por-NPs localised in hearts and detected increases in plaque size longitudinally with high-cholesterol diet. Por-NP fluorescence was visualized in aortic sinus plaques, co-localised with CD68 macrophages, and by fluorescence IVIS imaging in aortic arch plaque. In two murine models, Por-NP-treated mice had smaller early-stage (22 %) and unstable plaques (52 %). Por-NP-treated mice had fewer circulating (32 %) and aortic (81 %) monocytes, and lower mRNA levels of aortic arch (26 %) and (27 %),  < 0.05. CONCLUSIONS: Por-NPs detect plaques using multiple imaging modalities and exhibit atheroprotective effects, presenting as novel nanoscale theranostics for atherosclerosis.