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preprint

Single-cell phenomics through integrated imaging and molecular profiling

Bues, Johannes Julius  
•
Pezoldt, Jörn  
•
Lambert, Camille Lucie Germaine  
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December 1, 2025

Single-cell technologies such as transcriptomics, microscopy, and flow cytometry have revolutionized the study of cellular identity and function. While each of these technologies is powerful on its own, their full potential lies in their integration, enabling multimodal profiling of the same cell and revealing how distinct modalities influence one another. Here, we introduce IRIS (Interconnected Robotic Imaging and Single cell transcriptomics), a deterministic single-cell platform technology that seamlessly couples high-resolution microscopy with droplet-based single-cell RNA sequencing. IRIS enables precise cell positioning, multimode imaging across brightfield and fluorescent channels, and subsequent molecular capture from the same cell, directly linking high-resolution morphological features to matched transcriptomes. We validate IRIS by recovering cell cycle progression states and transcriptional programmes associated with canonical morphologies and demonstrate its discovery power by molecularly resolving two nuclear-ER architectures within naïve CD8 + T cells, each defined by distinct gene expression profiles and functional markers. IRIS establishes an integrative single-cell phenomics framework, opening new avenues for dissecting how cellular form relates to molecular state and function.

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Type
preprint
DOI
10.1101/2025.11.28.690954
Author(s)
Bues, Johannes Julius  

EPFL

Pezoldt, Jörn  

EPFL

Lambert, Camille Lucie Germaine  

EPFL

Hale, Benjamin David
Bugani, Elisa
Vinas Torne, Ramon
Ferrari, Timothée  

EPFL

Grenningloh, Nadia
Gardeux, Vincent  

EPFL

Wen, Shuo  

EPFL

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Date Issued

2025-12-01

Publisher

Cold Spring Harbor Laboratory

Written at

EPFL

EPFL units
UPDEPLA  
LHTC  
UPKARTHAUS  
FunderFunding(s)Grant NumberGrant URL

Swiss National Science Foundation

TMAG29 3_209335

Precision Health and Related Technologies

PHRT-573

Swiss National Science Foundation

CRSK-3_190627

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Available on Infoscience
December 4, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/256695
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