How Selective are Nanomaterials to Treat Osteoarthritis

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Yunpeng Zhang,1 Xinkun Cheng,1 Jiwei Tian,1 Jian Liu,1 Yuanyin Teng,2 Junhao Chen,3 Zhu Wu,4 Huimin Ding,1 Zhongsong Zhang5 1Department of Orthopedics, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210019, People’s Republic of China; 2Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China; 3Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China; 4The Hunan Provincial Key Laboratory of the TCM Agricultural Biogenomics, Changsha Medical University, Changsha, Hunan, 410219, People’s Republic of China; 5School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610550, People’s Republic of ChinaCorrespondence: Huimin Ding; Zhongsong Zhang, Email Dinghuimin1981@163.com; zzscmc1122@163.comAbstract: Osteoarthritis (OA) is now increasingly recognized as a disease that affects the entire joint, where synovial inflammation plays a key role in pain, cartilage degeneration, and structural progression. Synovial macrophages (SMs) are key regulators in this process due to their phenotypic plasticity and central roles in amplifying inflammation, disrupting immunometabolism, and interacting with other joint-resident cells. These characteristics make SMs attractive targets for disease-modifying interventions. However, conventional therapies are limited by poor intra-articular retention, low cellular selectivity, and inadequate control over complex pathogenic networks. This review summarizes the biological functions of SMs in OA and explains why they are a mechanistically important and therapeutically accessible target. Next, we provide a structured overview of nanomaterial-based strategies for SM-targeted OA therapy, covering major material platforms, receptor-guided delivery approaches, subset- and state-selective targeting, intracellular functional intervention, and multi-target combination designs. We highlight representative studies that show how nanomedicines can improve local retention, enhance macrophage-specific uptake, and modulate inflammation, metabolism, oxidative stress, and cell fate. Finally, we discuss the major barriers to clinical translation, such as macrophage heterogeneity, safety, pharmacokinetics, and chemistry, manufacturing, and controls (CMC), and outline future directions for biomarker-guided and precision nanotherapy in OA.Keywords: osteoarthritis, synovial inflammation, synovial macrophages, nanomedicine, precision therapy, nanocarriers

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