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Physiological principles underlying the kidney targeting of renal nanomedicines

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Kidney disease affects more than 10% of the global population and is associated with considerable morbidity and mortality, highlighting a need for new therapeutic options. Engineered nanoparticles for the treatment of kidney diseases (renal nanomedicines) represent one such option, enabling the delivery of targeted therapeutics to specific regions of the kidney. Although they are underdeveloped compared with nanomedicines for diseases such as cancer, findings from preclinical studies suggest that renal nanomedicines may hold promise. However, the physiological principles that govern the in vivo transport and interactions of renal nanomedicines differ from those of cancer nanomedicines, and thus a comprehensive understanding of these principles is needed to design nanomedicines that effectively and specifically target the kidney while ensuring biosafety in their future clinical translation. Herein, we summarize the current understanding of factors that influence the glomerular filtration, tubular uptake, tubular secretion and extrusion of nanoparticles, including size and charge dependency, and the role of specific transporters and processes such as endocytosis. We also describe how the transport and uptake of nanoparticles is altered by kidney disease and discuss strategic approaches by which nanoparticles may be harnessed for the detection and treatment of a variety of kidney diseases.

Key points

  • Despite considerable advances in cancer nanomedicines, renal nanomedicines for the treatment of kidney diseases are markedly underdeveloped.

  • The physiological principles that regulate the glomerular filtration, tubular secretion, luminal tubular uptake and re-elimination of nanoparticles in the kidneys may facilitate the selective targeting of nanoparticles to specific segments of the nephron.

  • Targeting of nanoparticles to different cell types in the glomerulus or to the glomerular basement membrane can be achieved through fine-tuning of their physicochemical properties based on our understanding of glomerular filtration and the glomerular filtration barrier.

  • Different transport pathways can be used to deliver nanoparticles to different components of the renal tubules, including the luminal and the basolateral sides of tubular epithelial cells and the interstitium.

  • Differences in nanoparticle transport and interactions between healthy and diseased kidney tissues offer opportunities for the design of nanoparticles that can selectively target specific kidney diseases.

  • A newly discovered organelle extrusion mechanism facilitates the elimination of endocytosed nanoparticles from the kidneys and may minimize the nephrotoxicity of future nanomedicines.

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Fig. 1: Glomerular filtration of nanoparticles.
Fig. 2: Representative nanoparticles eliminated by the kidneys through glomerular filtration.
Fig. 3: Tubular secretion and luminal tubular uptake of nanoparticles.
Fig. 4: Representative nanoparticles that are processed by the kidney tubules.
Fig. 5: Representative nanomedicines that target the glomerulus.
Fig. 6: Targeting of nanoparticles to proximal tubules in the healthy and injured kidney.
Fig. 7: Representative nanomedicines that target the renal tubules and interstitium.
Fig. 8: Proximal tubular extrusion of endocytosed gold nanoparticles by proximal tubule epithelial cells.

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Acknowledgements

The authors acknowledge support from the National Institutes of Health (NIH) (R01DK124881 (J.Z), R01DK115986 (J.Z), R01DK126140 (M.Y.)), and the Distinguished Chair of Natural Sciences & Mathematics (to J.Z.) from The University of Texas at Dallas.

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  1. Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX, USA

    Yingyu Huang, Xuhui Ning, Samira Ahrari, Mengxiao Yu & Jie Zheng

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Qi Cai

  3. Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Nilum Rajora & Ramesh Saxena

  4. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Jie Zheng

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Y.H. and J.Z. researched data for the article. Y.H., X.N., S.A., M.Y. and J.Z. contributed substantially to discussion of the content. Y.H., M.Y. and J.Z. wrote the article. Y.H., Q.C., N.R., R.S., M.Y. and J.Z. reviewed and/or edited the manuscript before submission.

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Huang, Y., Ning, X., Ahrari, S. et al. Physiological principles underlying the kidney targeting of renal nanomedicines. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00819-z

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