# Novel PMVs/ZIP4/Zinc/Prelamin A Axis Promotes Nuclear Dysmorphism and Vascular Aging in Humans and Rodents Post‐Injury: Effective Treatment With Platelet Membrane‐Coated ZIF‐8 Nanoparticles

## TL;DR

This study shows that vascular injury causes nuclear shape changes and aging, which can be treated with special nanoparticles.

## Contribution

The discovery of a new PMVs/ZIP4/Zinc/prelamin A pathway causing vascular aging and a novel nanoparticle treatment.

## Key findings

- PMVs reduce zinc levels, impairing prelamin A processing and causing nuclear dysmorphism.
- ZIP4 deficiency contributes to zinc depletion and vascular aging.
- Platelet membrane-coated Zn-MOF nanoparticles effectively treat nuclear dysmorphism and aging.

## Abstract

Interventional therapy and surgery play important roles in the treatment of various diseases, but they cause varying degrees of vascular injury. Currently, the side effects are often overlooked. Here, we observed abnormal nuclear morphology (nuclear dysmorphism) and vascular aging in injured human and rodent arteries. Platelet‐derived microvesicles (PMVs) adhere to injured blood vessels, leading to nuclear dysmorphism and cell senescence in vascular smooth muscle cells (VSMCs). This occurs because PMV adherence reduces intracellular Zn2+ levels, which impairs Zn2+‐dependent processing of prelamin A by the enzyme ZMPSTE24. Consequently, prelamin A accumulates in VSMCs, contributing to the observed nuclear dysmorphism and cell senescence. RNA sequencing and loss‐of‐function assays revealed that Zinc transporter solute carrier family 39 member 4 (SLC39A4, also called ZIP4) deficiency accounts for the decreased Zinc concentration. Consistently, Zmpste24
+/− and Zmpste24
−/− mice displayed significant cumulative prelamin A, deteriorated nuclear dysmorphism and vascular aging. Whole genome bisulfite sequencing (WGBS) and bioinformatic analysis illustrated that demethylation of genes within Lamina‐associated domains (LADs) participates in nuclear dysmorphism and cell senescence. Of note, Zinc supplementation, especially using platelet membrane‐coated Zn‐MOF nanoparticles, robustly alleviated nuclear dysmorphism and vascular aging. Our data established a novel and significant role of pMVs/ZIP4/zinc/prelamin A axis in promoting nuclear dysmorphism and vascular aging after injury.

Interventional therapy and surgical injury induce nuclear dysmorphism and vascular aging. Nuclear dysmorphism is positively associated with vascular aging. Novel PMVs/ZIP4/Zinc/preLamin A axis plays a key role in injury‐induced nuclear dysmorphism and vascular aging. Platelet membrane‐coated Zn‐MOF nanoparticles are a potential way in treating nuclear dysmorphism and vascular aging post‐injury.