Beyond Targeted Delivery: The Emerging Immunomodulatory Landscape of Antibody-Oligonucleotide Conjugates
- 1Department of Laboratory Medicine, Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin 132013, China
Abstract
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.
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BibTeX
@article{wang2026beyond,
title = {{Beyond Targeted Delivery: The Emerging Immunomodulatory Landscape of Antibody-Oligonucleotide Conjugates}},
author = {Yangyang Wang and Shaonan Wang and Huiyan Wang},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209274},
url = {https://www.mdpi.com/1422-0067/27/20/9274},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond Targeted Delivery: The Emerging Immunomodulatory Landscape of Antibody-Oligonucleotide Conjugates
AU - Yangyang Wang
AU - Shaonan Wang
AU - Huiyan Wang
PY - 2026
DA - 2026/10/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209274
UR - https://www.mdpi.com/1422-0067/27/20/9274
AB - 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.
SN - 1422-0067
ER -