Osteoarthritis is a whole-joint disease characterized by persistent inflammation, immune dysregulation, oxidative stress, cellular senescence, and impaired cartilage repair. Current treatments remain largely symptomatic, underscoring the need for disease-modifying strategies that can reshape the pathological joint microenvironment. Nanoimmunomodulation offers a promising approach by combining targeted intra-articular delivery, controlled release, biomimetic design, and immune reprogramming. In this Review, we discuss how nanoplatforms, including polymeric nanoparticles, lipid vesicles, inorganic nanozymes, extracellular vesicle-inspired systems, cell-membrane-coated nanoparticles, and hydrogel-nanoparticle composites, regulate synovial macrophage polarization, inflammasome activation, ROS accumulation, mitochondrial dysfunction, ferroptosis, cellular senescence, and cartilage matrix catabolism. We further propose a translational framework linking nanomaterial design to disease-stage-specific immune phenotypes, joint retention, cartilage penetration, safety, manufacturability, and clinically meaningful endpoints. While nanoimmunomodulation offers a compelling preclinical rationale for targeting multiple pathological drivers simultaneously, its translation into clinically validated disease-modifying therapy remains contingent upon overcoming significant hurdles in safety, manufacturing, and regulatory endpoint alignment. This review proposes a phenotype-driven framework to guide future clinical development rather than asserting imminent clinical efficacy.
