siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA

Area of Science:

• Nanomedicine
• Renal cell biology
• Gene therapy

Background:

• Chronic kidney disease (CKD) lacks effective therapies to halt or reverse its progression.
• Small interfering RNA (siRNA) nanoparticles offer targeted gene silencing for potential CKD treatment.
• The kidney glomerulus is an accessible site for nanoparticle delivery.

Purpose of the Study:

• To investigate the feasibility of using polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) for targeted delivery to the glomerular mesangium.
• To assess the biodistribution and cellular uptake of siRNA/CDP-NPs in the kidney.
• To demonstrate the therapeutic potential of siRNA/CDP-NPs for gene silencing in mesangial cells.

Main Methods:

• Intravenous administration of siRNA/CDP-NPs in a mouse model.
• Biodistribution analysis to determine nanoparticle localization within the kidney.
• In vitro studies using mouse and human mesangial cells to assess nanoparticle internalization.
• Evaluation of enhanced green fluorescent protein (eGFP) knockdown in a reporter mouse strain.

Main Results:

• siRNA/CDP-NPs demonstrated preferential localization to the glomerular mesangium with minimal off-target deposition.
• Mesangial cells (both mouse and human) rapidly internalized siRNA/CDP-NPs in vitro.
• Targeting ligands (mannose, transferrin) enhanced nanoparticle uptake by mesangial cells.
• Successful knockdown of mesangial eGFP expression was achieved following intravenous siRNA/CDP-NP treatment.

Conclusions:

• Intravenously administered siRNA/CDP-NPs are feasible for targeted delivery to the glomerular mesangium.
• This approach holds potential for developing novel siRNA-based therapies for chronic kidney disease.
• Targeted delivery of therapeutic payloads to kidney cells is achievable using engineered nanoparticles.