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  • Review Article
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Subcutaneous drug delivery from nanoscale systems

Nature Reviews Bioengineering (2024)Cite this article

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Abstract

Various types of nanoscale drug delivery systems (DDSs) have been developed for therapeutic and/or diagnostic applications. However, most systems have been designed for intravenous or intramuscular delivery, which may have drawbacks such as pain during injection, the inability for self-administration and the requirement for hospitalization, causing patient discomfort and high treatment costs. The subcutaneous route of administration is an attractive approach to circumvent many of these drawbacks. However, the subcutaneous route remains underexplored and is not yet used to its full potential. In this Review, we present key advances in the design of nanoscale DDSs (polymer–drug conjugates, liposomes, nanoparticles, micelles) for subcutaneous delivery. Additionally, we discuss nanoscale DDS-loaded hydrogels to create drug depots after subcutaneous administration, and outline relevant predictive in vitro, ex vivo, in silico and in vivo preclinical models for subcutaneous delivery. Finally, we highlight subcutaneous nanoscale DDSs in clinical trials and on the market and outline translational opportunities.

Key points

  • Subcutaneous (SC) drug delivery can bypass limitations of intravenous and intramuscular administration, particularly in terms of patient comfort, treatment costs and drug delivery modalities.

  • The SC Drug Delivery & Development Consortium, composed of academic and industry experts, has identified opportunities in SC drug delivery development to improve and extend the applications of SC technology.

  • SC delivery can be applied to a range of nanoscale drug delivery systems (DDSs), including polymer–drug conjugates, liposomes, nanoparticles, micelles and hydrogel-embedded nanoscale DDSs.

  • By specifically designing nanoscale DDSs for SC delivery, different therapeutic effects can be obtained, such as lymph node targeting, rapid systemic absorption, sustained release of drugs from the SC tissue and vaccination.

  • Several nanoscale DDSs for SC delivery have reached the clinical trial stage and some are available on the market.

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Fig. 1: Anatomy of the skin and comparison of administration routes.
Fig. 2: Polymer–drug conjugates and liposomes for subcutaneous administration.
Fig. 3: Nanoscale drug delivery system-loaded thermosensitive hydrogels for subcutaneous administration.
Fig. 4: Comparison of the main preclinical models for subcutaneous administration.

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Acknowledgements

The PhD fellowships of L.T. and M.F. and some results described in this Review have been funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 771829). The National Centre for Scientific Research (CNRS) and Université Paris-Saclay are also acknowledged for the financial support.

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Authors and Affiliations

  1. Institut Galien Paris-Saclay, Université Paris-Saclay, CNRS, Orsay, France

    Lorenzo Tomasini, Marianne Ferrere & Julien Nicolas

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  1. Lorenzo Tomasini
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  2. Marianne Ferrere
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All authors contributed equally to the preparation of this manuscript.

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Correspondence to Julien Nicolas.

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J.N. is a co-founder of the startup company Imescia. The other authors have no competing interests.

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Related links

EpiDerm: https://www.mattek.com/products/epiderm

EpiSkin/Human Epidermis: https://www.episkin.com/Episkin

Genoskin. HypoSkin - Skin model for subcutaneous injections: https://genoskin.com/en/tissue-samples/skin-model-subcutaneous-injections

Subcutaneous Drug Development & Delivery Consortium: https://subcutaneousconsortium.org

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Tomasini, L., Ferrere, M. & Nicolas, J. Subcutaneous drug delivery from nanoscale systems. Nat Rev Bioeng (2024). https://doi.org/10.1038/s44222-024-00161-w

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