Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.
Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.
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使用脂质体的小干扰RNA（siRNA）的阴道滴注已经导致生殖道中内源性基因的沉默，并保护免受感染性疾病的挑战。虽然siRNA脂质复合物容易配制，但几种市售的最有效的转染剂可能对粘膜上皮细胞有毒，并且没有一种能够提供控释或缓释。在这里，我们展示了一种替代方法，使用完全由FDA批准的材料组成的纳米颗粒。为了使这些材料对基因沉默有效，我们开发了新的方法来用大量的siRNA加载它们。向小鼠雌性生殖道单剂量的siRNA负载的纳米颗粒引起有效和持续的基因沉默。在局部给药部位的近端（阴道腔）和远端（子宫角）观察到基因表达的敲低。此外，纳米颗粒深入上皮组织。这是第一份证明可生物降解的聚合物纳米颗粒是阴道粘膜中siRNA的有效递送载体的报告。
Vaginal instillation of small-interfering RNA (siRNA) using liposomes has led to silencing of endogenous genes in the genital tract and protected against challenge from infectious disease. Although siRNA lipoplexes are easily formulated, several of the most effective transfection agents available commercially may be toxic to the mucosal epithelia and none are able to provide controlled or sustained release. Here, we demonstrate an alternate approach, using nanoparticles composed entirely of FDA-approved materials. To render these materials effective for gene silencing we developed novel approaches to load them with high amounts of siRNA. A single dose of siRNA-loaded nanoparticles to the mouse female reproductive tract caused efficient and sustained gene silencing. Knockdown of gene expression was observed proximal (in the vaginal lumen) and distal (in the uterine horns) to the site of topical delivery. In addition, nanoparticles penetrated deep into the epithelial tissue. This is the first report demonstrating that biodegradable polymer nanoparticles are effective delivery vehicles for siRNA in the vaginal mucosa.
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