National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
School of Stomatology, Zhejiang Chinese Medicine University, Hangzhou 310053, China.
Acta Biomater. 2021 Aug;130:435-446. doi: 10.1016/j.actbio.2021.05.024. Epub 2021 Jun 3.
Metabolic skeletal disorders remain a major clinical challenge. The complexity of this disease requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. Herein, we describe a microRNA-21 (miR-21) delivery system with an additional therapeutic effect from that of the delivery carrier itself. Poly (salicylic acid) (PSA) is, for the first time, synthesized via polycondensation of salicylic acid (SA), a bioactive ingredient widely used for anti-inflammation in medicine. PSA can self-assemble into nanoparticles (PSA-NPs) and can effectively deliver genes both in vitro and in vivo. The carrier was then attached to repetitive sequences of aspartate, serine, serine (DSS) for delivering miRNAs specifically to bone-formation surfaces. In vitro studies showed that miR-21@PSA-NP could effectively realize the intracellular delivery of miR-21 with low toxicity, while in vivo results indicated that the miR-21@PSA-NP-DSS prolonged blood circulation time, enhanced bone accumulation, and significantly improved the efficacy of miR-21-based bone anabolic therapy in osteoporotic mice. The constructed delivery system (miR-21@PSA-NP-DSS) inherited the advantages of both SA and miR-21, which could ameliorate bone-inflamed niche and rescued the impaired bone formation ability. The synergy of anti-inflammatory and pro-osteogenic effects significantly improved trabecular bone microstructure in osteoporotic mice. STATEMENT OF SIGNIFICANCE: The complexity of metabolic skeletal disorders requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. We develop a novel microRNA-21 delivery system with additional therapeutic effect from that of the gene carrier itself. Poly (salicylic acid) (PSA) nanoparticles, for the first time, synthesized via polycondensation of salicylic acid and can effectively deliver genes both in vitro and in vivo. The constructed delivery system (miR-21@PSA-NP-DSS) inherited the advantages of both SA (commonly used anti-inflammation drug in medicine) and miR-21 (a pro-osteogenic molecule), which could ameliorate bone-inflamed niche, rescued impaired bone formation ability and significantly improved trabecular bone microstructure in osteoporotic mice.
代谢性骨骼疾病仍然是一个主要的临床挑战。这种疾病的复杂性需要一种策略来解决炎症和骨形成受损的净效应。基于 microRNA 的基因治疗为解决这些问题提供了多种治疗优势。在这里，我们描述了一种 microRNA-21 (miR-21) 递药系统，该系统具有除递药载体本身之外的额外治疗效果。聚（水杨酸）（PSA）首次通过水杨酸（SA）的缩聚合成，SA 是一种广泛用于医学抗炎的生物活性成分。PSA 可以自组装成纳米颗粒（PSA-NPs），并可以在体外和体内有效地递送基因。然后，该载体被连接到天冬氨酸、丝氨酸、丝氨酸（DSS）的重复序列上，以将 miRNAs 特异性递送到成骨表面。体外研究表明，miR-21@PSA-NP 可以有效地实现 miR-21 的细胞内递药，同时具有低毒性，而体内结果表明，miR-21@PSA-NP-DSS 延长了血液循环时间，增强了骨积累，并显著改善了 miR-21 基于骨质疏松症小鼠的成骨治疗效果。所构建的递药系统（miR-21@PSA-NP-DSS）继承了 SA 和 miR-21 的优势，可改善炎症性骨龛，并挽救受损的成骨能力。抗炎和促成骨作用的协同作用显著改善了骨质疏松症小鼠的小梁骨微观结构。
代谢性骨骼疾病的复杂性需要一种策略来解决炎症和骨形成受损的净效应。基于 microRNA 的基因治疗为解决这些问题提供了多种治疗优势。我们开发了一种新型的 microRNA-21 递药系统，该系统具有除基因载体本身之外的额外治疗效果。聚（水杨酸）（PSA）纳米颗粒，首次通过水杨酸的缩聚合成，可在体外和体内有效地递送基因。所构建的递药系统（miR-21@PSA-NP-DSS）继承了 SA（医学上常用的抗炎药物）和 miR-21（促成骨分子）的优势，可改善炎症性骨龛，挽救受损的成骨能力，并显著改善骨质疏松症小鼠的小梁骨微观结构。
