Bioengineered Integration and Organization of Cellular Archives into Confined Historical Entities

Ziel

Single-cell RNA sequencing and spatial transcriptomics have revolutionized biomedical research by deepening our understanding of gene expression profiles and cellular heterogeneity underlying development, tissue homeostasis, and disease. However, true longitudinal -omics approaches where temporal information is encoded in the same subject rather than inferred via cross-sectional sampling are still scarce; most available approaches based on metabolic labeling essentially collapse dynamics in two timepoints and cannot capture extended trajectories. Furthermore, spatial -omics methods encoding temporal information are largely missing. To fill this gap, I propose the development of BIO-CACHE: a generalizable, genetically encoded ‘nano-storage platform’–a ‘flight recorder’ for cells–enabling ‘subject locked’, temporally-resolved -omics. BIO-CACHE can be deployed at user defined time points to capture and store biomolecular snapshots of interest. Timestamped molecular states stored within BIO-CACHE can be later retrieved and temporally resolved to reconstruct chronological trajectories of the underlying biological events. To build BIO-CACHE, we will leverage bio-orthogonal capsid scaffolds, which will be functionalized with internal capture domains for RNA or proteins, and outward-facing, self-labelling protein tags enabling fluorescent time-stamping via brief ligand pulses. We will implement bulk and imaging-based spatial readouts for BIO-CACHE and connect with microwell-based single-cell workflows, enabling spatiotemporally-resolved molecular profiling across biological scales. BIO-CACHE fills a critical methodological gap by recording many timepoints over days in the same subject for true 4D-omics without cross-sectional confounds. By augmenting existing -omics with a temporal axis, BIO-CACHE will unlock unprecedented insights into cellular dynamics, advancing our ability to decipher complex biological systems and paving new avenues for therapeutic breakthroughs.

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