In recent years, antibody‑drug conjugates (ADCs) have achieved remarkable advances and accomplishments in clinical research. Owing to their precise targeting mechanisms and compelling clinical data, ADCs have emerged as vital therapeutic options in oncology. Compared with ADCs, antibody‑oligonucleotide conjugates (AOCs) represent an emerging research modality that effectively combines the delivery capability of antibodies with the sequence‑specific gene‑regulatory functions of oligonucleotides. AOCs hold promise for alleviating the systemic cytotoxic side effects commonly observed with ADCs and offer a novel strategy for extra‑hepatic targeted delivery.
1. Structure and Components of AOCs
AOCs are bifunctional molecules formed by conjugating gene‑modulating oligonucleotides to targeting antibodies via linkers. They are designed to achieve efficient intracellular delivery of oligonucleotides to specific cells for precise modulation of target gene expression. Structurally analogous to antibody‑drug conjugates, AOCs consist of three building blocks: antibody, linker, and active payload.
1.1 Antibody Moiety
In AOC design, the antibody component is far more than a simple targeting moiety. The selection of antibody format (e.g., full‑length IgG or Fab fragment) constitutes a core strategic decision that exerts profound impacts on targeting efficiency, pharmacokinetics, safety profile and ultimate therapeutic outcomes. Antibody format selection requires trade‑offs among four key factors: payload properties, biological microenvironment of target tissues, desired pharmacological effects, and immunogenicity risks. Two major technical strategies are currently predominant: engineered full‑length IgG antibodies and smaller antigen‑binding fragments. Companies including Avidity Biosciences and Dyne Therapeutics, both targeting TfR1, have adopted distinctly different antibody design approaches, providing illustrative comparative case studies for rational AOC design.
1.2 Therapeutic Target Selection
Therapeutic target selection for AOCs is primarily governed by the tissue distribution specificity and endocytic kinetics of target receptors. Well‑validated targeting receptors are critical to successful AOC development: they serve as the “navigation system” for precise oligonucleotide delivery to target cells and directly determine the therapeutic potential of candidate molecules. To date, studies and applications of receptors such as TfR1, ASGPR, CD22 and SIRPα have preliminarily demonstrated the therapeutic potential of antibody‑nucleic acid conjugates across multiple disease areas, including hematological malignancies, solid‑tumor immunotherapy, inherited muscular disorders and liver diseases. Additional target antigens include CD33, EGFR, HER2, CD44, CD29, Nectin‑4 and PSMA.
1.3 Active Payloads
Active payloads for antibody‑oligonucleotide conjugates mainly comprise small‑interfering RNA (siRNA), antisense oligonucleotides (ASOs), phosphorodiamidate morpholino oligomers (PMOs), and immunostimulatory oligonucleotides (e.g., TLR9 agonist T‑CpG).
Unmodified oligonucleotides suffer from poor biological stability, susceptibility to nuclease degradation and limited cellular uptake. Therefore, chemical modifications are essential to improve stability, in‑vivo distribution and therapeutic efficacy. Common modification strategies include phosphate backbone modification, full‑length modification, base modification and sugar‑ring modification. At the 2′‑position of sugar moieties, 2′‑O‑methylation (2′‑OMe) is widely used to enhance nuclease resistance, reduce immunostimulation and improve thermal stability; locked nucleic acid (LNA) modifications strengthen hybridization affinity and structural stability.
1.4 Linkers and Conjugation Strategies
Linker stability dictates whether payloads are specifically released within target cells or prematurely dissociate in circulation, which would cause off‑target effects. Linkers are categorized into cleavable and non‑cleavable types. Cleavable linkers encompass Val‑Cit, disulfide bonds, tripeptide (CX) motifs and phosphate groups. Non‑cleavable linkers include SMCC, amide bonds, DBCO‑nitroso, alkyne‑nitroso, and BCN‑nitroso chemistries.
The core functions of AOC linkers are payload protection and delivery: they ensure intact nucleic acid transport to the cytosol of target cells and prevent degradation. By contrast, ADC linkers are optimized for rapid toxin release to trigger tumor‑cell killing. Accordingly, AOCs generally adopt low‑to‑moderate drug‑to‑antibody ratios (DAR/OAR, typically 2‑4), since high loading accelerates systemic clearance. Oligonucleotides such as siRNA possess unique physicochemical features: large molecular size, strong negative charge and high hydrophilicity. These properties have driven the development of four major core conjugation strategies distinct from the direct covalent conjugation predominantly used for conventional ADCs: direct covalent conjugation, electrostatic‑mediated complexation, biotin‑streptavidin bridging, and hybridization‑mediated assembly.
2. Mechanism of Action of AOCs
Fundamental differences in delivery objectives and payload properties give rise to distinct design principles for AOCs relative to ADCs. The therapeutic performance of AOCs is not determined solely by target binding affinity; of greater importance is completion of the full intracellular delivery cascade: receptor‑mediated internalization, endosomal escape, payload liberation, and functional access of payloads to cytoplasmic or nuclear target sites.
Antibody‑oligonucleotide conjugates bind to specific cell‑surface antigens via their antibody domain and trigger receptor‑mediated endocytosis, entering early endosomes, late endosomes or lysosomes. Depending on linker structure and properties, cleavage occurs at different stages of endosomal maturation. Such cleavage facilitates oligonucleotide escape from endosomal compartments to exert pharmacological effects.
3. Global Clinical R&D Progress
As an emerging therapeutic modality, AOCs are witnessing robust global research momentum. As of July 2026, 64 AOC programs are at various developmental stages worldwide, among which seven candidates have advanced into clinical trials. These programs mainly target rare diseases, cancer and neurodegenerative disorders.
Delpacibart etedesiran (AOC 1001), developed by Avidity Biosciences, has entered Phase III clinical trials for myotonic dystrophy type 1. This RNAi therapeutic incorporates an anti‑transferrin receptor 1 (TfR1) antibody to enable targeted oligonucleotide delivery. Other AOC candidates from Avidity Biosciences, including delpacibart braxlosiran (AOC 1020) for facioscapulohumeral muscular dystrophy and delpacibart zotadirsen (AOC 1044) for Duchenne muscular dystrophy, are also in Phase III trials. The advancement of these therapeutics highlights the technical strengths of AOCs for neuromuscular degenerative diseases.
DYNE‑101, engineered by Dyne Therapeutics for myotonic dystrophy type 1, conjugates an anti‑TfR1 Fab fragment to an ASO to achieve muscle‑specific delivery. DYNE‑251 (z‑rostudirsen), also from Dyne Therapeutics, couples PMO to a TfR1‑targeting Fab fragment. DYNE‑251 is designed for targeted muscle delivery and induces exon skipping in the nucleus to produce truncated yet functional dystrophin protein in muscle cells, for Duchenne muscular dystrophy patients eligible for exon 51 skipping. In May 2026, Dyne Therapeutics submitted a BLA to the FDA for z‑rostudirsen (DYNE‑251), alongside initiation of the Phase III FORZETTO study. DYNE‑101 remains in Phase III clinical development.
TAC‑001 from Tallac Therapeutics is currently in Phase I/II clinical trials for solid tumors. TAC‑001 targets CD22 and incorporates a TLR9 agonist payload to potentiate immune responses.
Collectively, current AOC clinical development is most heavily concentrated on neuromuscular rare diseases, with expanding pipelines toward oncology and central nervous system disorders.
4. Current Challenges and Future Opportunities
AOCs represent novel therapeutics integrating two complex molecular classes: antibodies and oligonucleotides. Their R&D and manufacturing face multiple challenges, including endosomal escape bottlenecks, trade‑offs between target engagement and delivery efficiency, limited tissue coverage, immunological safety concerns, as well as process development and quality‑control complexities. Successful AOC development is not a simple theoretical ligation of antibodies and oligonucleotides. Instead, it requires systematic, multi‑dimensional investigation of new variables arising from the combination of two mature but disparate technological systems.
Nevertheless, the AOC field is evolving from isolated technical breakthroughs toward platform‑driven and intelligence‑guided development. Future success will hinge on intelligent integration of diversified delivery modalities together with cutting‑edge therapeutic approaches such as disease‑specific gene editing, empowered by AI‑driven rational design throughout the workflow. Such deep interdisciplinary integration positions AOCs as promising next‑generation precision therapeutics.
