Xu Xiao-Ling, Xue Yan, Ding Jia-Ying, Zhu Zhi-Heng, Wu Xi-Chen, Song Yong-Jia, Cao Yue-Long, Tang Long-Guang, Ding Dao-Fang, Xu Jian-Guang
Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, China.
Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), School of Medicine, Tongji University, Shanghai 201613, China.
Acta Biomater. 2022 Dec;154:23-48. doi: 10.1016/j.actbio.2022.10.007. Epub 2022 Oct 12.
Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.
骨关节炎（OA）是一种退行性关节疾病，是成年人慢性疼痛和功能残疾的主要原因。关节软骨是一种含水的软组织，由低密度的正常静止软骨细胞、孔径为60 - 200纳米的致密胶原纤维网络以及带高密度负电荷的聚集蛋白聚糖组成。尽管某些药物、核酸和蛋白质有减缓OA进展并恢复关节功能的潜力，但由于缺乏能够突破软骨屏障的有效递送系统，这些治疗方法尚未在临床上应用。最近，用于递送系统的纳米技术发展为克服有限的穿透性带来了新的思路和治疗方法。在本综述中，我们重点关注纳米技术此类应用的当前研究，包括外泌体、基于蛋白质的阳离子纳米载体、阳离子脂质体/固体脂质纳米粒、基于氨基酸的纳米载体、基于聚酰胺衍生物的纳米载体、二氧化锰和碳纳米管。外泌体是已知最小的纳米级细胞外囊泡，它们可以将核酸或蛋白质快速递送至所需深度。通过静电相互作用，在阳离子性质和粒径方面具有适当平衡的纳米载体具有很强的穿透软骨的能力。尽管已经获得了大量临床前证据，但临床转化仍需要进一步优化。重要性声明：具有高负电荷的致密软骨基质与深部病理改变的骨关节炎患者治疗效果降低有关。然而，仍缺乏对用于深层软骨穿透的纳米装置的系统综述。本文综述了目前确保纳米系统穿透软骨深度的方法，包括来自不同细胞系的纳米级细胞外囊泡以及在阳离子性质和粒径方面具有适当平衡的纳米载体。此外，还讨论了进入临床试验的纳米装置及其进一步优化，为未来研究提供了重要的指导意义。
