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Strategies for non-viral vectors targeting organs beyond the liver

Nature Nanotechnology volume 19, pages 428–447 (2024)Cite this article

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Abstract

In recent years, nanoparticles have evolved to a clinical modality to deliver diverse nucleic acids. Rising interest in nanomedicines comes from proven safety and efficacy profiles established by continuous efforts to optimize physicochemical properties and endosomal escape. However, despite their transformative impact on the pharmaceutical industry, the clinical use of non-viral nucleic acid delivery is limited to hepatic diseases and vaccines due to liver accumulation. Overcoming liver tropism of nanoparticles is vital to meet clinical needs in other organs. Understanding the anatomical structure and physiological features of various organs would help to identify potential strategies for fine-tuning nanoparticle characteristics. In this Review, we discuss the source of liver tropism of non-viral vectors, present a brief overview of biological structure, processes and barriers in select organs, highlight approaches available to reach non-liver targets, and discuss techniques to accelerate the discovery of non-hepatic therapies.

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Fig. 1: Barriers to non-viral gene delivery in the eyes and lungs.
Fig. 2: Anatomy of extrahepatic targets.
Fig. 3: Toolbox for non-viral gene delivery research.
Fig. 4: Schematic of directed evolution of NP formulation for extrahepatic targeting.

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Acknowledgements

We thank funding from the National Eye Institute 1R01EY033423-01A1 (G.S.), the National Heart Lung and Blood Institute (NHLBI) R01HL146736-01 (G.S) and SAHAY 19XX0 (G.S), and the National Cancer Institute 1R01CA270783-01 (G.S).

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  1. These authors contributed equally: Jeonghwan Kim, Yulia Eygeris.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA

    Jeonghwan Kim, Yulia Eygeris, Antony Jozić & Gaurav Sahay

  2. College of Pharmacy, Yeungnam University, Gyeongsan, South Korea

    Jeonghwan Kim

  3. Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA

    Renee C. Ryals & Gaurav Sahay

  4. Department of Biomedical Engineering, Robertson Life Sciences Building, Oregon Health and Science University, Portland, OR, USA

    Gaurav Sahay

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Contributions

G.S. conceived the idea and provided critical feedback. J.K. and Y.E. drafted the initial manuscript. J.K., Y.E., R.C.R. and A.J. created the figures and tables. All authors contributed to the writing of the paper. J.K. and Y.E. revised the paper with input from all authors. All authors have given approval to the entire content of this paper and its submission.

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Correspondence to Gaurav Sahay.

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Competing interests

G.S. serves as an advisor to Rare Air Inc and RNAvax Bio. G.S. is a co-founder of EnterX Bio and Y.E. has stock options and an advisory role with EnterX Bio. EnterX Bio has a scientific research agreement with OSU. G.S. has a conflict management plan at OSU. The other authors declare no competing interests.

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Kim, J., Eygeris, Y., Ryals, R.C. et al. Strategies for non-viral vectors targeting organs beyond the liver. Nat. Nanotechnol. 19, 428–447 (2024). https://doi.org/10.1038/s41565-023-01563-4

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