Black TiO2 nanoprobe-mediated mild phototherapy reduces intracellular lipid levels in atherosclerotic foam cells via cholesterol regulation pathways instead of apoptosis

Ting Dai; Wenming He; Shuangshuang Tu; Jinru Han; Bo Yuan; Chenyang Yao; Wenzhi Ren; Aiguo Wu

doi:10.1016/j.bioactmat.2022.01.013

Black TiO₂ nanoprobe-mediated mild phototherapy reduces intracellular lipid levels in atherosclerotic foam cells via cholesterol regulation pathways instead of apoptosis

Bioact Mater. 2022 Jan 17:17:18-28. doi: 10.1016/j.bioactmat.2022.01.013. eCollection 2022 Nov.

Authors

Ting Dai¹, Wenming He¹, Shuangshuang Tu^{1

2}, Jinru Han^{2

3

4}, Bo Yuan^{2

4}, Chenyang Yao^{2

4}, Wenzhi Ren^{2

4}, Aiguo Wu^{2

4}

Affiliations

¹ Department of Cardiology, The Affiliated Hospital of Medical School, Ningbo University, 247 Renmin Road, Jiangbei District, Ningbo, Zhejiang Province, 315020, China.
² Cixi Institute of Biomedical Engineering, International Cooperation Base of Biomedical Materials Technology and Application, CAS Key Laboratory of Magnetic Materials and Devices & Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, 1219 ZhongGuan West Road, Ningbo, 315201, China.
³ University of Chinese Academy of Sciences, No. 1 Yanqihu East Road, Huairou District, Beijing, 101408, China.
⁴ Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516000, China.

Abstract

Given that apoptosis increases the risk of plaque rupture, strategies that reduce intracellular lipid levels without killing foam cells are warranted for safe and effective treatment of atherosclerosis. In this study, a mild phototherapy strategy is carried out to achieve the hypothesis. Foam cell-targeted nanoprobes that allow photothermal therapy (PTT) and/or photodynamic therapy (PDT) were prepared by loading hyaluronan and porphine onto black TiO₂ nanoparticles. The results showed that when temperatures below 45 °C, PTT alone and PTT + PDT significantly reduced the intracellular lipid burden without inducing evidently apoptosis or necrosis. In contrast, the use of PDT alone resulted in only a slight reduction in lipid levels and induced massive apoptosis or necrosis. The protective effect against apoptosis or necrosis after mild-temperature PTT and PTT + PDT was correlated with the upregulation of heat shock protein 27. Further, mild-temperature PTT and PTT + PDT attenuated intracellular cholesterol biosynthesis and excess cholesterol uptake via the SREBP2/LDLR pathway, and also triggered ABCA1-mediated cholesterol efflux, ultimately inhibiting lipid accumulation in foam cells. Our results offer new insights into the mechanism of lipid regulation in foam cells and indicate that the black TiO₂ nanoprobes could allow safer and more effective phototherapy of atherosclerosis.

Keywords: Atherosclerosis; Black TiO2 nanoparticles; Cholesterol homeostasis; Phototherapy.