2. Academic Validation
  3. In Situ Reprogramming of Senescent Microenvironment via Augmentation of Endogenous Senolytic Actions for Advanced Atherosclerosis Management

In Situ Reprogramming of Senescent Microenvironment via Augmentation of Endogenous Senolytic Actions for Advanced Atherosclerosis Management

  • ACS Nano. 2025 Dec 23. doi: 10.1021/acsnano.5c17402.
Zhiyue Wang 1,  Xing Chen 2,  Yutong Xu 3 4,  Xiang Guo 1,  Xingji Liu 5,  Ximei Dai 6,  Jiaqi Lu 6,  Jianchen Qi 1,  Tao Zheng 1,  Linlin Zhang 1,  Long Ma 1,  Sheng Wang 7,  Guifen Yang 6,  Guangming Lu 1,  Feng Wang 3,  Qing Zhou 2,  Jie Sheng 1,  Longjiang Zhang 1
Affiliations

Affiliations

  • 1 Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
  • 2 Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China.
  • 3 Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
  • 4 Department of Nuclear Medicine, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China.
  • 5 Department of Radiology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210008, China.
  • 6 Department of Nuclear Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, China.
  • 7 Department of Radiology, Nanjing Jinling Hospital, Nanjing Medical University, 305 East Zhongshan Road, Nanjing 210002, China.
PMID: 41431968 DOI: 10.1021/acsnano.5c17402
Abstract

Advanced atherosclerosis (AS) poses substantial residual risk of life-threatening Cardiovascular Disease, even with optimized lipid-lowering therapies. Histopathological evaluation of clinically obtained specimens revealed that advanced plaques developed a distinct senescent microenvironment compared to early stage lesions, and senescent foam cells (FCs) are the culprits in creating the pathological microenvironment via initiating senescence-propagating crosstalk with multiple vascular cells. Herein, we synthesized a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine denoted as L-pKNZ. Unlike conventional senolytic agents that primarily induce cellular Apoptosis, L-pKNZ activates FC Autophagy and enhances macrophage efferocytosis. This strategy established an endogenous senolytic system to relieve FC overload while simultaneously reprogramming the senescent microenvironment. Results from multiomics analysis aligned with outcomes from in vitro/in vivo experiments, all in favor of vascular rejuvenation and AS amelioration. Critically, we successfully radiolabeled L-pKNZs with the radionuclide 68Ga, which allowed noninvasive in vivo imaging of the senescent microenvironment with micro-PET/CT. Overall, this study provides a versatile theranostic platform with broad implications for age-related diseases.

Keywords

PET/CT imaging; ZIF-8 nanoparticles; advanced atherosclerosis; autophagy; efferocytosis; senescence.

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