A recent review published in Bioconjugate Chemistry by Marinier et al. (2026) shows that DNA-encoded libraries (DELs), long established for therapeutic small-molecule discovery, represent an underutilized yet highly promising platform for the rapid, parallel development of next-generation molecular probes – particularly for live-cell imaging, targeted radioimaging, and personalized theranostics. DEL-derived targeting moieties can be efficiently and modularly converted into high-affinity, high-selectivity optical or radiolabeled probes – including dual-use agents that simultaneously enable precise diagnosis and effective therapy (Figure 1).A recent review published in Bioconjugate Chemistry by Marinier et al. (2026) shows that DNA-encoded libraries (DELs), long established for therapeutic small-molecule discovery, represent an underutilized yet highly promising platform for the rapid, parallel development of next-generation molecular probes – particularly for live-cell imaging, targeted radioimaging, and personalized theranostics. DEL-derived targeting moieties can be efficiently and modularly converted into high-affinity, high-selectivity optical or radiolabeled probes – including dual-use agents that simultaneously enable precise diagnosis and effective therapy (Figure 1).

Figure 1. DEL for new molecular probe discovery

1. Trends in molecular probe development

Conventional probes include several different types of structures. Non-targeted fluorescent dyes were developed and used in early years, but that resulted in high background and poor selectivity. Metabolic radiotracers like [¹⁸F]FDG lack target specificity. Bi-functional tracers with large targeting moiety (larger peptides, aptamers and antibodies) suffer from limited tissue penetration, instability, and complex manufacturing. Small molecules targeting moiety offer compelling advantages – as targeting ligands, they provide excellent cell permeability, metabolic stability, oral bioavailability potential, shelf life, and scalable synthesis – making them ideal scaffolds for bi-functional probes. An effective approach to discover suitable small molecules for probe development is in urgent need.

2. Development of DEL technology and its role in new probe discovery

DEL technology has undergone rapid development over the past few decades. Various DEL construction strategies (e.g., dsDEL, ssDEL, Dynamic DEL, OBOC-DEL), DNA-compatible chemistries (amide coupling, Suzuki cross-coupling, reductive amination), screening modalities (target-immobilized pulldown, live-cell selection, target-agnostic cell-based assays), and hit validation workflows (on-DNA/off-DNA resynthesis, FP, SPR, ELISA) have been reported. These advances enabled ultra-high-throughput screening of billions of compounds against diverse, challenging targets – including membrane proteins, intracellular targets, whole cells, pathogens, mRNA, and even patient-derived samples. The DNA tag acts as a robust, solvent-exposed conjugation handle – enabling rational, modular reporter attachment without compromising binding affinity. Highly selective molecules arise from DEL’s vast chemical diversity and compatibility with counter-screening (e.g., antitarget cells), while rapid screening (<1 week) makes fast probe development possible.

3. DEL-derived molecular probe development cases

The following figure shows some examples of DEL hit-based probe discovery (Figure 2). Some of them exhibit promising prospects:

• CAIX (Carbonic Anhydrase IX)-targeting optical probe: 3b (Kd = 7 nM) enabled ex vivo tumor imaging and successfully guided CAIX-expressing SK-RC-52 tumor lysis in the presence of fluorescein-specific UniCAR T-cells;
• PSMA (Prostate-Specific Membrane Antigen)-targeting probes: 7b/8b showed nanomolar affinity, high selectivity over antitarget GCP3 (glutamate carboxypeptidase III), and selective cellular internalization; 7c demonstrated reduced kidney uptake compared with Pluvicto® treatment to mitigate nephrotoxicity;
• CAIX-targeting radioactive probes: [¹⁷⁷Lu]-labeled 6d achieved near-exclusive tumor accumulation in xenografts; [⁶⁸Ga]-labeled 6e is currently in Phase I clinical trial for renal cancer.

Figure 2. Left: Structures of validated DEL hits against known cancer-associated antigens (R = DNA exit vector). Right: Structure of the optimized probes.

4. Future directions and summary

The successful cases shown above prove the potential of DEL-based new molecular probe development. Some challenges still need to be addressed, including cost and access barriers for DELs, as well as low retention and short circulation half-life. Commercial DEL products like HitGen OpenDEL™, as well as academic DEL platforms, will democratize the access to high-quality DELs. Predictive models can be built based on integration of AI/ML to extract structure-affinity relationships from DEL data. Broader adoption of covalent DEL binders (e.g., acrylamide warheads) will help enhance retention and theranostic efficacy. Incorporation of albumin-binding motifs is beneficial for extending circulation half-life. Ultimately, DEL is positioned as a foundational, data-rich, and highly adaptable technology uniquely suited to accelerate the development of personalized, next-generation molecular probes and theranostics.

Reference:

Julien Poupart, Sunit Kumar Jana, Sasmita Tripathy, and Anne Marinier. DNA-Encoded Libraries (DELs) for Discovering New Molecular Probes: Application to Live-Cell Bioimaging and Personalized Theranostics. Bioconjugate Chem. 2026, 37, 3, 511–525. https://pubs.acs.org/doi/10.1021/acs.bioconjchem.5c00661