Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan.
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
J Control Release. 2022 Jul;347:590-606. doi: 10.1016/j.jconrel.2022.05.032. Epub 2022 May 28.
Psoriasis is an autoimmune skin disorder presenting the excessive expression of interleukin (IL)-6. The topical use of small interfering RNA (siRNA) has been increasingly discovered for treating skin diseases. A delivery system capable of protecting siRNA while facilitating both skin targeting and cellular entrance is critical for the successful medication of topically-applied siRNA. Herein, we developed a delivery system for siRNA based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles and combined this system with an ablative laser to promote skin absorption for topical psoriasis therapy. The siRNA absorption enhancement was compared by two laser modalities: a fractional CO laser and a fully-ablative Er:YAG laser. We characterized the effect of the delivery system by the cellular uptake, IL-6 silencing, in vitro skin absorption, cutaneous biodistribution, and in vivo psoriasiform dermatitis in mice. The nanocarriers showed minimal cytotoxicity and facile cellular uptake to knock down the IL-6 expression. The nanoformulation containing a cationic surfactant (Forestall) for ion pairing with siRNA achieved a 66% and 77% IL-6 knockdown efficiency toward keratinocytes and macrophages, respectively. In the Franz cell absorption, the lasers increased the naked siRNA penetration to the receptor compartment by 3.7-5.0-fold but remarkably reduced skin deposition using imiquimod (IMQ)-treated psoriasiform skin as the barrier. The fractional laser facilitated nanoparticle-associated siRNA skin deposition up to 3.3-fold, whereas the transport of the nanocarriers to the receptor was negligible. Qualitatively, the lasers increased nanoparticle delivery in the epidermis with limited effect to elevate the penetration depth. The fractional-mediated nanocarrier delivery dramatically attenuated the erythema and scaly lesions of psoriasiform dermatitis. The histological examination displayed a reduction of epidermal hyperplasia and macrophage infiltration by the combination of laser and nanosystem. The passive and laser-assisted naked siRNA delivery was less effective in mitigating dermatitis. The topical delivery of fractional laser-assisted nanoparticles on mice resulted in a 56% IL-6 knockdown. Our results manifested the benefit of cutaneous siRNA targeting using ablative lasers to deliver nanocarriers for treating psoriatic inflammation.
银屑病是一种自身免疫性皮肤疾病，表现为白细胞介素 (IL)-6 的过度表达。小干扰 RNA (siRNA) 的局部应用越来越多地被发现可用于治疗皮肤疾病。一种能够保护 siRNA 同时促进皮肤靶向和细胞进入的递送系统对于成功应用局部应用的 siRNA 至关重要。本文中，我们开发了一种基于聚（乳酸-共-乙醇酸）（PLGA）纳米粒子的 siRNA 递送系统，并将该系统与消融激光相结合，以促进皮肤对局部银屑病治疗的吸收。通过两种激光模式：分数 CO2 激光和全消融 Er:YAG 激光，比较了 siRNA 的吸收增强效果。我们通过细胞摄取、IL-6 沉默、体外皮肤吸收、皮肤组织分布和小鼠体内银屑病样皮炎来表征递送系统的效果。纳米载体表现出最小的细胞毒性和易于摄取的细胞摄取能力，可降低 IL-6 的表达。含有阳离子表面活性剂（Forestall）用于与 siRNA 离子配对的纳米制剂分别实现了对角质形成细胞和巨噬细胞的 66%和 77%的 IL-6 敲低效率。在 Franz 细胞吸收中，激光将裸 siRNA 穿透受体隔室的能力提高了 3.7-5.0 倍，但使用咪喹莫特 (IMQ) 处理的银屑病样皮肤作为屏障时，显著减少了皮肤沉积。分数激光促进了纳米载体相关 siRNA 皮肤沉积增加了 3.3 倍，而纳米载体向受体的输送可以忽略不计。从定性上看，激光增加了表皮中的纳米载体传递，但对增加穿透深度的影响有限。分数介导的纳米载体输送可显著减轻银屑病样皮炎的红斑和鳞屑病变。组织学检查显示，激光和纳米系统联合使用可减少表皮过度增生和巨噬细胞浸润。被动和激光辅助裸 siRNA 传递在减轻皮炎方面效果较差。局部递送至小鼠的分数激光辅助纳米颗粒导致 56%的 IL-6 敲低。我们的结果表明，使用消融激光靶向皮肤中的 siRNA 来递送纳米载体治疗银屑病炎症具有益处。
