Abstract
BACKGROUND: Recent advances in immunotherapy have spotlighted macrophages as central mediators of disease treatment. Their polarization into pro‑inflammatory (M1) or anti‑inflammatory (M2) states critically influences outcomes in cancer, autoimmunity, and chronic inflammation. Oligonucleotides have emerged as highly specific, scalable, and cost‑effective agents for reprogramming macrophage phenotypes. OBJECTIVE: To review oligonucleotide strategies-including ASOs, siRNAs, miRNA mimics/inhibitors, and aptamers-for directing macrophage polarization and their therapeutic implications. REVIEW SCOPE: We examine key signaling pathways governing M1/M2 phenotypes, describe four classes of oligonucleotides and their mechanisms, and highlight representative preclinical and clinical applications. KEY INSIGHTS: Agents such as AZD9150, MRX34, and AS1411 demonstrate macrophage reprogramming in cancer, inflammation, and infection models. Advances in ligand‑conjugated nanoparticles and chemical modifications improve delivery and stability, yet immunogenicity, off‑target effects, and formulation challenges remain significant barriers. FUTURE PERSPECTIVES: Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation.