Gao Yunzhen, Jia Na, Liang Yi, Xu Yani, Shi Rongying, Long Jiaying, Lin Qing, Zhang Zhirong, Zhang Ling, Huang Shiqi
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Med-X Center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China.
Nanoscale. 2025 Jul 3;17(26):16025-16038. doi: 10.1039/d5nr01696g.
Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disorder with high disability and teratogenic rates. The cause of RA remains elusive, and no specific treatment target has been identified yet. Natural sinomenine hydrochloride (SIN) has the potential to control the progression of RA. However, it suffers from limited bioavailability and unfavored biodistribution, leading to increased dosage and administration frequency, which in turn lead to adverse reactions. In this study, we engineered natural ferritin as a delivery vehicle for SIN, adding the CD24 functional fragment (Ser27-Gly59) on its surface (CD24-PfFn). Ferritin is highly biocompatible and exhibits passive targeting capability the ELVIS effect. The attached CD24 on CD24-PfFn enables it to bind with immunosuppressive receptors Siglec-10 on the B cells and DAMPs in the pathological synovial fluid. This interaction results in both targeted accumulation of CD24-PfFn at the RA site and effective blockage of the downstream immune activation response, enhancing inflammation selectivity. With a simple depolymerization/self-assembly process, SIN could be effectively loaded into CD24-PfFn to form CD24-PfFn-SIN. Animal experiments showed that CD24-PfFn-SIN was highly selective for RA inflammatory joints and significantly restrained the progression of RA and repaired cartilage damage and bone erosion. Hence, this CD24-PfFn-SIN system represents a promising targeted therapy for RA treatment. Moreover, our ferritin modification strategy is verified, and this strategy is versatile as a large pool of functional peptides could be explored for other applications.
类风湿性关节炎（RA）是一种慢性难治性自身免疫性疾病，致残率和致畸率很高。RA的病因尚不清楚，目前尚未确定具体的治疗靶点。天然盐酸青藤碱（SIN）有控制RA病情进展的潜力。然而，其生物利用度有限且生物分布不理想，导致用药剂量增加和给药频率提高，进而引发不良反应。在本研究中，我们设计将天然铁蛋白作为SIN的递送载体，在其表面添加CD24功能片段（Ser27 - Gly59）（CD24 - PfFn）。铁蛋白具有高度生物相容性，并表现出被动靶向能力即ELVIS效应。CD24 - PfFn上附着的CD24使其能够与B细胞上的免疫抑制受体Siglec - 10以及病理滑液中的损伤相关分子模式（DAMPs）结合。这种相互作用导致CD24 - PfFn在RA部位靶向积累，并有效阻断下游免疫激活反应，增强炎症选择性。通过简单的解聚/自组装过程，SIN能够有效地负载到CD24 - PfFn中形成CD24 - PfFn - SIN。动物实验表明，CD24 - PfFn - SIN对RA炎症关节具有高度选择性，并显著抑制RA病情进展，修复软骨损伤和骨侵蚀。因此，这种CD24 - PfFn - SIN系统代表了一种有前景的RA靶向治疗方法。此外，我们的铁蛋白修饰策略得到了验证，并且由于可以探索大量功能肽用于其他应用，该策略具有通用性。
