Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

Abstract

Accumulation of lipid-laden macrophages (foam cells) is characteristic of atherosclerosis development in the arterial walls. Ferritin nanocages have been found to passively accumulate in the atherosclerotic plaque. Ferritin has been actively investigated as a carrier for contrast agents in atherosclerosis diagnosis. We demonstrate the potential of ferritin as a carrier for therapeutic molecules to mediate cholesterol reduction from foam cells. Cyclodextrin molecules are chemically conjugated to the ferritin nanocages surface or encapsulated within the nanocages using metal co-loading methods. The cyclodextrin-conjugated ferritin has nanomolar affinity to cholesterol molecules. Treatment of foam cells with the conjugates shows decreased levels of intracellular accumulated cholesterol. The preferential localization of ferritin to foam cells is due to transferrin receptor-mediated endocytosis process. These findings show that ferritin nanocages as carriers localize cyclodextrin molecules to foam cells which mediate intracellular cholesterol reduction, thus highlighting its potential use as a therapeutic agent.

Targeting the Microenvironment of Vulnerable Atherosclerotic Plaques: An Emerging Diagnosis and Therapy Strategy for Atherosclerosis

“…Based on the high‐affinity receptors that are highly expressed in macrophages, nanomaterials modified with specific ligands can actively target macrophage‐rich lesions. A number of receptors, including folate receptors (FRs), [ 25a,80 ] mannose receptors (MRs), [ 81 ] and transferrin receptor 1 (TfR1), [ 82 ] have been reported to act as targets for activated macrophages in vulnerable atherosclerotic plaques. Liang et al.…”

“…Overexpressed Receptors on Activated Macrophages: Based on the high-affinity receptors that are highly expressed in macrophages, nanomaterials modified with specific ligands can actively target macrophage-rich lesions. A number of receptors, including folate receptors (FRs), [25a,80] mannose receptors (MRs), [81] and transferrin receptor 1 (TfR1), [82] have been reported to act as targets for activated macrophages in vulnerable atherosclerotic plaques. Liang et al utilized H-ferritin as an imaging nanoprobe, with excellent biocompatibility and high binding affinity with TfR1 to reflect the progression of AS (Figure 7a).…”

Protein nanoparticles in molecular, cellular, and tissue imaging

“…For example, heat shock protein nanocages and ferritin nanocages. Ferritin has been explored widely due to the ease of targeting transferrin receptors and enabling transferrin receptor-based uptake in plaque macrophages (Ravishankar & Lim, 2019).…”

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