Abstract: TH-PO0029
Kidney-Targeted siRNA Therapeutic Development for Fibrotic Kidney Diseases
Session Information
- Bioengineering: MPS, Flow, and Delivery
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bioengineering
- 400 Bioengineering
Authors
- Williams, Ryan, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
- Vasylaki, Anastasiia, The City College of New York, New York, New York, United States
- Ghosh, Pratyusha, The City College of New York, New York, New York, United States
- Arnaout, Adnan, The City College of New York, New York, New York, United States
- Baltaci, Melis, The City College of New York, New York, New York, United States
- Kulick, Amanda, Memorial Sloan Kettering Cancer Center, New York, New York, United States
- de Stanchina, Elisa, Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
Background
Tubulointerstitial fibrosis significantly contributes to the progression of chronic kidney disease (CKD), driven by factors such as cell death and inflammatory cytokine expression. Despite the growing global health and economic impacts of CKD, current treatments are limited, and none specifically target inflammation. This study evaluated the therapeutic efficacy of kidney-targeting nanoparticles delivering siRNA against key inflammatory drivers in two mouse models of fibrotic CKD.
Methods
Previously, we developed polymeric mesoscale nanoparticles (MNPs) designed to selectively target kidneys due to their size and surface properties. These particles selectively localize to proximal tubular epithelial cells, where they degrade and release their cargo gradually. In this study, we loaded MNPs with siRNA targeting the inflammatory cytokines IL-6 and IL-1β, the inflammation-regulating transcription factor ETS-1, and the inflammatory regulator mTOR, as well as a control scrambled siRNA sequence. We examined their therapeutic efficacy following intravenous injection in mouse model of unilateral uretral obstruction (UUO)-induced CKD and adenine-induced CKD. We assessed animal health, weight, kidney function, and fibrosis using trichrome staining to assess the effectiveness of targeted gene silencing.
Results
The MNPs optimized to encapsulate siRNA for each target and control sequence, were within the optimal 300 – 500 nm mesoscale range for effective kidney targeting. MNPs loaded with siRNA against IL-6 and ETS-1 showed a reduction in fibrosis in the UUO mouse model. Additionally, MNPs loaded with siRNA against mTOR demonstrated improved renal function and overall animal health in the adenine-induced CKD model.
Conclusion
We plan further pre-clinical development of these promising lead siRNA-MNP therapeutics by evaluating their biodistribution and efficacy in porcine and non-human primate animals, with the potential for clinical translation of these therapeutics
Funding
- Other NIH Support