Scholarlink

<p>Small interfering RNAs (siRNAs) offer significant therapeutic potential; however, extrahepatic applications, particularly to the skin, remain a challenge. Limited work has explored siRNA therapies for the skin, the largest organ in the human body, where dermatological conditions affect over one-third of the population worldwide. The skin’s external location makes it easily accessible for direct, local administration. Here, we present the in vivo intradermal delivery of therapeutic siRNAs into a porcine model whose skin structure most closely resembles that of human skin, demonstrating functional, and sustained gene silencing. We characterize two siRNA conjugates in human ex vivo and porcine in vivo skin models, showing that increased hydrophobicity significantly enhances skin retention and efficacy of siRNAs. Using a validated JAK1-targeting compound, we demonstrate that local delivery of siRNA enables accumulation across multiple cell types and suppression of JAK1-dependent inflammatory pathway in human skin ex vivo. In porcine models, intradermal injections result in prolonged skin siRNA retention for more than eight weeks, limited systemic tissue exposure, and sustained gene silencing for at least one month. These results underscore the importance of tailored siRNA conjugate design for achieving optimal skin biodistribution and therapeutic efficacy, providing a foundation for siRNA-based treatments for a broad range of dermatological conditions.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Intradermal delivery of lipophilic siRNAs enables prolonged skin retention and sustained gene silencing in a porcine model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月3日

查看全文
  • Hassan H. Fakih,
  • Mohammad Zain UI Abideen,
  • Mohamad Omar Rachid,
  • Katherine Y. Gross,
  • Thomas J. R. Ormsby,
  • Vella M. Ross,
  • Rosemary Gagnon,
  • Christopher Dahlke,
  • Raymond C. Furgal,
  • Clemens Lochmann,
  • Ashley Summers,
  • Hanadi F. Sleiman,
  • Sylvia M. Fürst,
  • Shanté N. Jackson,
  • Juliana O. Gordilho,
  • Claire Bouix-Peter,
  • Thibaud Portal,
  • Qi Tang,
  • John E. Harris,
  • Anastasia Khvorova,
  • Carine Blanchard,
  • Julia F. Alterman

摘要

Small interfering RNAs (siRNAs) offer significant therapeutic potential; however, extrahepatic applications, particularly to the skin, remain a challenge. Limited work has explored siRNA therapies for the skin, the largest organ in the human body, where dermatological conditions affect over one-third of the population worldwide. The skin’s external location makes it easily accessible for direct, local administration. Here, we present the in vivo intradermal delivery of therapeutic siRNAs into a porcine model whose skin structure most closely resembles that of human skin, demonstrating functional, and sustained gene silencing. We characterize two siRNA conjugates in human ex vivo and porcine in vivo skin models, showing that increased hydrophobicity significantly enhances skin retention and efficacy of siRNAs. Using a validated JAK1-targeting compound, we demonstrate that local delivery of siRNA enables accumulation across multiple cell types and suppression of JAK1-dependent inflammatory pathway in human skin ex vivo. In porcine models, intradermal injections result in prolonged skin siRNA retention for more than eight weeks, limited systemic tissue exposure, and sustained gene silencing for at least one month. These results underscore the importance of tailored siRNA conjugate design for achieving optimal skin biodistribution and therapeutic efficacy, providing a foundation for siRNA-based treatments for a broad range of dermatological conditions.