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

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Nanomedicine

Background:

• Advanced atherosclerosis (AS) presents significant cardiovascular disease risk despite lipid-lowering therapies.
• Senescent foam cells (FCs) create a pathological microenvironment in advanced plaques through cell crosstalk.
• Existing senolytic agents primarily induce apoptosis, limiting their therapeutic scope.

Purpose of the Study:

• To develop a novel nanomedicine (L-pKNZ) targeting senescent FCs in AS.
• To investigate L-pKNZ's mechanism of action, focusing on autophagy and efferocytosis.
• To establish a theranostic platform for imaging and treating the senescent microenvironment in AS.

Main Methods:

• Synthesis of a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine, L-pKNZ.
• In vitro and in vivo experiments assessing L-pKNZ's effects on FCs and vascular cells.
• Multiomics analysis to understand molecular mechanisms.
• Radiolabeling of L-pKNZ with ⁶⁸Ga for micro-PET/CT imaging.

Main Results:

• L-pKNZ activates FC autophagy and enhances macrophage efferocytosis, unlike traditional senolytics.
• This endogenous senolytic system effectively relieves FC overload and reprograms the senescent microenvironment.
• Experiments confirmed vascular rejuvenation and AS amelioration.
• ⁶⁸Ga-labeled L-pKNZ enabled noninvasive imaging of the senescent microenvironment.

Conclusions:

• L-pKNZ represents a novel therapeutic strategy for AS by targeting senescent FCs.
• The developed nanomedicine promotes vascular health through an endogenous senolytic system.
• This study presents a versatile theranostic platform for age-related diseases, with potential applications beyond AS.