Abstract
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.
Data availability
All data generated in this study are provided in the Supplementary Information and Source Data file. A Source Data file is provided with this paper. Source data are provided with this paper.
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Acknowledgments
This project was supported by the National Institutes of Health (grant R35 GM131839, S10 OD020012, and S10 OD036329 to A.K.; and Alys Pharmaceuticals/ Aldena Therapeutics (support to J.F.A).
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H.H.F., M.Z.U., Q.T., J.F.A., J.E.H., A.K., C.B., C.B.P., and T.P. conceived the project. H.H.F., M.Z.U., Q.T., J.F.A., A.K., S.F., S.J., C.B., C.B.P., and J.O.G. contributed to the experimental design. S.J. was the sole point of contact responsible for overseeing the conduct of studies at Altasciences. H.H.F., M.Z.U., and Q.T. contributed experimentally to human ex vivo studies, including flow cytometry and gene silencing. H.H.F., Q.T., M.Z.U., M.O.R., and K.Y.G. contributed experimentally to ex vivo human skin stimulation and downstream signaling. M.Z.U., V.R., K.Y.G., and R.G. contributed experimentally to siRNA accumulation in porcine organs. M.O.R. and T.J.R.O. contributed experimentally to porcine silencing, stimulation and downstream signaling. M.Z.U., Q.T., H.H.F., M.O.R., T.J.R.O., C.D., R.C.F., C.L., and A.S. helped with overall skin processing and experimental setup. H.H.F. synthesized all siRNA compounds used in the manuscript, with H.H.F. and H.F.S. contributing to the design of the dendritic siRNA conjugation. H.H.F., Q.T., M.Z.U., C.B., J.F.A., and A.K. wrote the manuscript. All authors provided feedback and approved the manuscript.
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The authors declare the following competing financial interest(s): The University of Massachusetts Chan Medical School holds patent or filed patent applications for the modulation of JAK1 with RNAi-based technologies (patent application number 18393044; Oligonucleotides for IFN-γ signaling pathway modulation; status pending), docosanoic acid conjugate (patent application number 17377632; Conjugated oligonucleotides for tissue-specific delivery) and dendritic conjugate for skin delivery (Patent application number 18592943; status pending). A.K. serves on the scientific advisory board of Alys Pharmaceuticals. J.E.H. owns equities in Rheos Medicines; is a founder of Alys Pharmaceuticals and Villaris Therapeutics. Select authors of this publication are listed as inventors on RNAi technology patents (HHF, M.Z.U., Q.T., J.F.A., J.E.H., A.K., M.Z.U., R.F., and K.G.) that have been licensed to biotech and pharmaceutical companies. The following patents are licensed by Aldena Therapeutics Ltd.: patent application number 18393044 (Oligonucleotides for IFN-γ signaling pathway modulation) and patent application number 17377632 (Conjugated oligonucleotides for tissue-specific delivery). C.B.P., C.B., J.O.G., and T.P. are executive employees of Alys Pharmaceuticals. SF is employed by Certara. SJ is employed by Altasciences. The remaining authors declare no competing interests.
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Fakih, H.H., Zain UI Abideen, M., Rachid, M.O. et al. Intradermal delivery of lipophilic siRNAs enables prolonged skin retention and sustained gene silencing in a porcine model. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68993-1
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DOI: https://doi.org/10.1038/s41467-026-68993-1
