Diabetic osteoporosis, a prevalent chronic complication of diabetes, is marked by reduced bone mass, increased bone fragility, and susceptibility to fractures. A significant cause of this condition is the disruption of osteoblastic homeostasis due to prolonged hyperglycemia, which impedes bone regeneration and remodeling. Despite its prevalence, no effective treatments specifically target diabetic osteoporosis. Recently, small-activating RNA (saRNA) therapy has attracted attention for its targeting capacity, high efficacy, and minimal side effects. However, RNA’s inherent properties, such as structural instability, susceptibility to degradation, and poor penetration, limit its applications. To address these limitations, a gene-activating tetrahedral framework nucleic acid (tFNA) with sirtuin-1 (SIRT1) gene activation function is developed, termed Tsa. Tsa exhibits an RNA-protecting effect and can effectively penetrate cell membranes to upregulate SIRT1 gene expression. At the histological level, Tsa treatment alleviates diabetic osteoporosis by increasing bone trabecular density and promoting new bone formation. At the cellular level, it switches macrophage polarization toward the anti-inflammatory M2 phenotype while inhibiting the inflammatory M1 phenotype, creating a favorable bone immune microenvironment for osteoblasts. At the genetic level, Tsa activates SIRT1 expression, which deacetylates Acetyl-p65 to block the NF-κB pathway and restore the osteoimmune environment. Overall, this research demonstrates a nanodrug “Tsa”, capable of activating SIRT1 and modulating the bone immune environment, thereby showcasing its immense potential for diabetic osteoporosis treatment.

中文翻译：

---

基因激活框架核酸靶向上调 sirtuin-1 调节骨免疫微环境，用于糖尿病骨质疏松症治疗


糖尿病性骨质疏松症是糖尿病的一种普遍的慢性并发症，其特点是骨量减少、骨脆性增加和易发生骨折。这种情况的一个重要原因是由于长期高血糖导致成骨细胞稳态的破坏，这阻碍了骨骼的再生和重塑。尽管糖尿病骨质疏松症很普遍，但没有专门针对糖尿病骨质疏松症的有效治疗方法。最近，小激活 RNA （saRNA） 疗法因其靶向能力、高疗效和最小的副作用而引起了人们的关注。然而，RNA 的固有特性，如结构不稳定、易降解和渗透性差，限制了其应用。为了解决这些限制，开发了一种具有 sirtuin-1 （SIRT1） 基因激活功能的基因激活四面体框架核酸 （tFNA），称为 Tsa。Tsa 具有 RNA 保护作用，可有效穿透细胞膜上调 SIRT1 基因表达。在组织学水平上，Tsa 治疗通过增加骨小梁密度和促进新骨形成来缓解糖尿病骨质疏松症。在细胞水平上，它将巨噬细胞极化转向抗炎 M2 表型，同时抑制炎性 M1 表型，为成骨细胞创造有利的骨免疫微环境。在基因水平上，Tsa 激活 SIRT1 表达，使乙酰基 p65 脱乙酰，阻断 NF-κB 通路并恢复骨免疫环境。总体而言，这项研究展示了一种纳米药物“Tsa”能够激活 SIRT1 并调节骨骼免疫环境，从而展示了其在糖尿病骨质疏松症治疗方面的巨大潜力。