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iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
Fengxiang Wang1,2,3,4,5,6, Cuiji Sun2,3,4, Tianshu William Wu1,2,3,4,5,6
1Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
Nature
|November 12, 2025
Summary
We developed in situ imaging proteomics via expansion (iPEX), a new untargeted spatial proteomics tool. iPEX maps proteins in tissues at high resolution, revealing early Alzheimer's disease changes and lipid metabolism disruptions.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Increasing development of spatial omics technologies.
- Need for untargeted protein localization at high spatial resolution and coverage.
- Limitations in current methods for comprehensive spatial proteomics.
Purpose of the Study:
- Introduce in situ imaging proteomics via expansion (iPEX) for untargeted spatial proteomics.
- Achieve high spatial resolution and coverage for protein mapping in tissues.
- Investigate early molecular changes in Alzheimer's disease models.
Main Methods:
- Integration of isotropic tissue magnification with MALDI mass spectrometry imaging.
- Application of iPEX to diverse tissues including retina, brain, intestine, and liver.
- Analysis of protein expression and localization at micrometre scale.
Main Results:
- iPEX provides scalable spatial resolution down to the micrometre scale with 10-100-fold increased sensitivity.
- Construction of high-precision spatial proteomic maps, visualizing single-cell layers and structures.
- Detection of 600-1,500 proteins at 1-5-µm effective pixel size across various tissues.
- Identification of early mitochondrial aberrancy in 5xFAD Alzheimer's disease mouse models.
- Downregulation of ACAA1, impacting long-chain polyunsaturated fatty acid biosynthesis, linked to neurodegeneration.
Conclusions:
- iPEX is a powerful tool for untargeted spatial proteomics at micrometre resolution.
- Revealed early molecular insights into Alzheimer's disease pathogenesis, including lipid metabolism.
- Demonstrated broad applicability of iPEX across diverse biological samples and research areas.
