CD47-targeted nano-immunotherapy for treatment of atherosclerosis

In this ongoing project funded by the American Heart Association, we
pursued the development of targeted nanotherapeutics to inhibit the
CD47/SIRPα immune checkpoint axis, a promising strategy for enhancing
macrophage-mediated clearance of diseased tissue in atherosclerosis. We
evaluated multiple nanoparticle and small-molecule combinations,
ultimately selecting a ferumoxytol (FMX) nanoparticle loaded with the
potent CD47 downregulator RRx-001 emerged as the lead nanotherapeutic
candidate. In vitro and in vivo imaging studies demonstrated that FMX
nanoparticles preferentially accumulate in macrophage-rich regions of
atherosclerotic plaques. Using fluorescently labeled FMX in ApoE−/− mice,
we showed selective deposition of nanoparticles in inflamed aortic
lesions. Fluorescence microscopy revealed colocalization of FMX with
macrophages (MAC-3+), confirming their cellular targeting specificity.
Quantitative analysis indicated significantly greater FMX uptake by
macrophages compared to endothelial and smooth muscle cells (p <
0.0001), validating the macrophage-targeting potential of this
nanoplatform. Preliminary therapeutic efficacy studies were conducted in
ApoE−/− mice fed a high-fat diet and treated weekly with saline, FMX
alone, or FMX loaded with CD47 inhibitors (FMX-CD47). After two months of
treatment, aortic plaque burden was evaluated via Oil Red O staining.
These pilot data suggest a potential role for FMX-CD47 formulations in
attenuating atherosclerotic progression, supporting further investigation
into this nanotherapeutic strategy.