Beyond Targeted Delivery: The Emerging Immunomodulatory Landscape of Antibody-Oligonucleotide Conjugates

Antibody-oligonucleotide conjugates (AOCs) are usually viewed as delivery vehicles that carry nucleic-acid payloads to defined cell populations for gene silencing or gene regulation. Existing reviews concentrate on delivery systems, tumour-directed therapy and extrahepatic oligonucleotide delivery, while the intrinsic immunomodulatory activity of AOCs has received far less attention. Conjugation couples antibody-mediated targeting with the innate immune-stimulating activity of the payload, a property that most current AOCs seldom exploit. This review repositions AOCs as active immune regulators. Three emerging immunoregulatory applications are examined in detail: vaccine-adjuvant construction, neutrophil-driven innate immune activation, and immunometabolic reprogramming. Structure-activity relationships linking AOC design to immune potency are summarized, and their immune mechanisms are distinguished from those of free oligonucleotides and unconjugated antibodies. Based on preclinical and in vitro evidence, AOCs act as multifunctional immunomodulators rather than passive cargo carriers. Two sources of immune activity are distinguished: direct immunostimulation by the conjugated payload, and effects secondary to targeted delivery. These findings still await clinical confirmation. Key barriers to translation, including conjugation efficiency, mechanistic gaps and manufacturing bottlenecks, are discussed. Prospective applications include engineered vaccines, anti-infective innate therapy, tumour microenvironment remodelling and autoimmune intervention, pending further validation. This review provides a conceptual framework for developing next-generation AOC-based immune adjuvants and precision immunotherapeutics.