Wang Qing, Peng Xiaole, Gao Xiaoting, Qin Yi, Li Wenhao, Wu Zebin, Lao Zhiqi, Gao Ang, Mao Ziyan, Xu Yaozeng, Chu Paul K, Zhao Xin, Geng Dechun, Wang Huaiyu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Adv Mater. 2025 May;37(18):e2500883. doi: 10.1002/adma.202500883. Epub 2025 Mar 19.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by excessive inflammation, pathological bone resorption, and systemic osteoporosis. It lacks effective treatment due to the complex pathogenesis. Gene therapy, especially targeted oligonucleotide (ON) delivery therapy, offers a new prospect for the precise treatment of RA. Nevertheless, the clinical application of ON delivery therapy still faces various challenges such as the rapid enzymolysis by RNAse, the lack of tissue targeting ability, difficulty in cell membrane penetration, and the incapability of endolysosomal escape. To address these issues, a novel kind of engineered peptide and oligonucleotide (PON) nanohybrids are designed and fabricated, which provide various advantages including good biosafety, inflammatory region-targeted delivery, cell membrane penetration, reactive oxygen species (ROS) scavenging, and endolysosomal escape. The PON nanohybrids produce promising effects in suppressing inflammatory responses and osteoclastogenesis of macrophages via multiple signaling pathways. In vivo administration of PON nanohybrids not only ameliorates local joint bone destruction and systemic osteoporosis in the pathological state, but also demonstrates good prophylactic effects against the rapid progression of RA disease. In conclusion, the study presents a promising strategy for precise RA treatment and broadens the biomedical applications of gene therapy based on delivery system.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为过度炎症、病理性骨吸收和全身性骨质疏松。由于发病机制复杂，它缺乏有效的治疗方法。基因治疗，尤其是靶向寡核苷酸（ON）递送疗法，为RA的精准治疗提供了新的前景。然而，ON递送疗法的临床应用仍面临各种挑战，如被RNA酶快速酶解、缺乏组织靶向能力、细胞膜穿透困难以及无法从内溶酶体逃逸。为了解决这些问题，设计并制备了一种新型的工程化肽与寡核苷酸（PON）纳米杂交体，其具有多种优势，包括良好的生物安全性、炎症区域靶向递送、细胞膜穿透、活性氧（ROS）清除以及内溶酶体逃逸能力。PON纳米杂交体通过多种信号通路在抑制巨噬细胞的炎症反应和破骨细胞生成方面产生了有前景的效果。在体内施用PON纳米杂交体不仅改善了病理状态下局部关节骨破坏和全身性骨质疏松，还对RA疾病的快速进展显示出良好的预防作用。总之，该研究为RA的精准治疗提出了一种有前景的策略，并拓宽了基于递送系统的基因治疗的生物医学应用。
