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Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury. | LitMetric

AI Article Synopsis

  • Acute kidney injury (AKI) is a sudden decline in kidney function affecting more people globally, and RNA interference (RNAi) shows promise as a treatment where traditional options are limited.
  • Researchers developed a new siRNA carrier using chitosan modified with α-cyclam-p-toluic acid (C-CS) to target injured kidneys and enhance delivery of RNAi therapy specifically to cells that overexpress the CXCR4 receptor.
  • In experiments, nanoparticles carrying siRNA against p53 (sip53) were found to effectively accumulate in damaged kidneys, reducing renal injury and inflammation, thereby highlighting the potential of C-CS/siRNA for treating AKI.

Article Abstract

Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133205PMC
http://dx.doi.org/10.1016/j.biomaterials.2022.121562DOI Listing

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