New review explores antibody-oligonucleotide conjugates: from ultrasensitive proteomics to targeted gene regulation

Antibody-oligonucleotide conjugates (AOCs) combine the high specificity of antibodies with the programmability of nucleic acids, creating a versatile molecular platform for both clinical diagnostics and targeted RNA therapy. A new review in LabMed Discovery provides an integrated overview of how AOC design has evolved and how these conjugates are being applied in protein analysis, multi-omics and therapeutic delivery.

The review first examines the building blocks and conjugation strategies of AOCs, tracing the field from random lysine- and cysteine-based coupling to more precise, site‑specific approaches that leverage engineered amino acids, Fc glycans, peptide tags, and unnatural amino acids. Particular attention is paid to how conjugation site, oligonucleotide-to-antibody ratio (OAR), linker properties and spatial configuration influence product homogeneity and functional performance.

In diagnostics, AOCs convert antigen recognition into amplifiable, sequence-readable nucleic acid signals. The review follows the technical progression from early immuno-PCR assays to proximity-dependent methods (e.g., PLA/PEA), sequencing-compatible proteomic workflows (e.g., CITE-seq, REAP-seq), and spatially resolved imaging platforms (e.g., CODEX).  These approaches expand the capacity to measure low-abundance proteins, multiplex biomarker panels and integrate protein information with single-cell or spatial data. Potential clinical applications include neurodegenerative and acute neurological biomarkers, cancer liquid biopsy, and inflammatory or infectious disease monitoring.

The therapeutic section focuses on antibody-guided delivery of antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and phosphorodiamidate morpholino oligomers (PMOs). Muscle-directed TfR1 AOCs represent the most clinically advanced branch, while tumor- and central nervous system-directed systems remain at earlier stages of translation.

The authors also highlight key barriers to broader clinical adoption, including productive intracellular delivery, endosomal escape, safety, immunogenicity, manufacturing consistency and analytical quality control. By providing an integrated view of molecular design, analytical performance, and clinical translation across both domains, this review aims to guide laboratory professionals, diagnostic developers, and therapeutic researchers in adopting and advancing AOC-based tools for precision medicine.