Peptide‐Oligonucleotide Nanohybrids Designed for Precise Gene Therapy of Rheumatoid Arthritis,Advanced Materials

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Peptide‐Oligonucleotide Nanohybrids Designed for Precise Gene Therapy of Rheumatoid Arthritis
Advanced Materials ( IF 27.4 ) Pub Date : 2025-03-19 , DOI: 10.1002/adma.202500883
Qing Wang ₁ , Xiaole Peng _{1,

2} , Xiaoting Gao ₃ , Yi Qin ₁ , Wenhao Li ₁ , Zebin Wu ₁ , Zhiqi Lao ₃ , Ang Gao ₃ , Ziyan Mao ₄ , Yaozeng Xu ₁ , Paul K Chu ₅ , Xin Zhao ₆ , Dechun Geng ₁ , Huaiyu Wang _{3,

7,

8}

Affiliation

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.

中文翻译：

肽-寡核苷酸纳米杂交体设计用于类风湿性关节炎的精确基因治疗

类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是过度炎症、病理性骨吸收和系统性骨质疏松症。由于发病机制复杂，它缺乏有效的治疗。基因治疗，尤其是靶向寡核苷酸（ON）递送治疗，为 RA 的精确治疗提供了新的前景。尽管如此，ON 递送疗法的临床应用仍面临各种挑战，例如 RNAse 的快速酶解、缺乏组织靶向能力、细胞膜穿透困难以及内溶酶体逃逸能力。为了解决这些问题，设计并制备了一种新型的工程肽和寡核苷酸（PON）纳米杂交体，它们具有良好的生物安全性、炎症区域靶向递送、细胞膜穿透、活性氧（ROS）清除和内溶酶体逃逸等优点。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有希望的效果。PON 纳米杂交体的体内给药不仅改善了病理状态下的局部关节骨破坏和系统性骨质疏松症，而且对 RA 疾病的快速发展也显示出良好的预防作用。综上所述，该研究为精准 RA 治疗提供了一种有前途的策略，并拓宽了基于递送系统的基因治疗的生物医学应用。

更新日期：2025-03-19

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