Theranostics 2022; 12(9):4200-4220. doi:10.7150/thno.70896 This issue

Research Paper

Inflammatory endothelium-targeted and cathepsin responsive nanoparticles are effective against atherosclerosis

Fei Fang1,2, Yinghao Ni1, Hongchi Yu1, Hongmei Yin3, Fan Yang1, Chunli Li1, Denglian Sun1, Tong Pei1, Jia Ma1, Li Deng1, Huaiyi Zhang1, Guixue Wang4, Song Li2✉, Yang Shen1✉, Xiaoheng Liu1✉

1. Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.
2. Department of Bioengineering and Department of Medicine, University of California, Los Angeles, Los Angeles 90001, USA.
3. West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
4. Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400030, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Fang F, Ni Y, Yu H, Yin H, Yang F, Li C, Sun D, Pei T, Ma J, Deng L, Zhang H, Wang G, Li S, Shen Y, Liu X. Inflammatory endothelium-targeted and cathepsin responsive nanoparticles are effective against atherosclerosis. Theranostics 2022; 12(9):4200-4220. doi:10.7150/thno.70896. Available from

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Graphic abstract

Rationale: Atherosclerosis is characterized by lipid accumulation, plaque formation, and artery stenosis. The pharmacological treatment is a promising therapy for atherosclerosis, but this approach faces major challenges such as targeted drug delivery, controlled release, and non-specific clearance.

Methods: Based on the finding that the cathepsin k (CTSK) enzyme is enriched in atherosclerotic lesions, we constructed an integrin αvβ3 targeted and CTSK-responsive nanoparticle to control the release of rapamycin (RAP) locally. The targeted and responsive nanoparticles (T/R NPs) were engineered by the self-assembly of a targeting polymer PLGA-PEG-c(RGDfC) and a CTSK-sensitive polymer PLGA-Pep-PEG. PLGA-Pep-PEG was also modified with a pair of FRET probe to monitor the hydrolysis events.

Results: Our results indicated that RAP@T/R NPs accelerated the release of RAP in response to CTSK stimulation in vitro, which significantly inhibited the phagocytosis of OxLDL and the release of cytokines by inflammatory macrophages. Additionally, T/R NPs had prolonged blood retention time and increased accumulation in the early and late stage of atherosclerosis lesions. RAP@T/R NPs significantly blocked the development of atherosclerosis and suppressed the systemic and local inflammation in ApoE-/- mice.

Conclusions: RAP@T/R NPs hold a great promise as a drug delivery system for safer and more efficient therapy of atherosclerosis.

Keywords: atherosclerosis, cathepsin k, nanoparticles, rapamycin, drug delivery