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Engineering precision nanoparticles for drug delivery

Nature Reviews Drug Discovery volume 20, pages 101–124 (2021)Cite this article

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Abstract

In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers — systemic, microenvironmental and cellular — that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

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Fig. 1: Biological barriers to precision medicine applications.
Fig. 2: Classes of NPs.
Fig. 3: NP characteristics impact distribution.
Fig. 4: Common uptake pathways that ultimately determine NP fate within a cell.
Fig. 5: Commonly engineered NP surface properties that allow for enhanced delivery.

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Acknowledgements

M.J.M. acknowledges support from a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a grant from the American Cancer Society (129784-IRG-16-188-38-IRG), the NIH (NCI R01 CA241661, NCI R37 CA244911 and NIDDK R01 DK123049), an Abramson Cancer Center (ACC)–School of Engineering and Applied Sciences (SEAS) Discovery Grant (P30 CA016520) and a 2018 American Association for Cancer Research (AACR)–Bayer Innovation and Discovery Grant (Grant Number 18-80-44-MITC). N.A.P. acknowledges support from the UT–Portugal Collaborative Research Program (CoLAB), the NIH (R01-EB022025-4 and R01-EB-00246-21), the National Science Foundation (Grant 1033746), the Pratt Foundation, the Cockrell Family Regents Chair and NSF Graduate Research Fellowships. R.M.H. was supported by a National Science Foundation (NSF) Graduate Research Fellowship (DGE 1845298). M.M.B. was supported by an NIH Training in HIV Pathogenesis T32 Program (T32 AI007632).

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Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell, Margaret M. Billingsley & Rebecca M. Haley

  2. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  3. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  4. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  5. Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  6. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA

    Marissa E. Wechsler & Nicholas A. Peppas

  7. Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA

    Nicholas A. Peppas

  8. Department of Pediatrics, The University of Texas at Austin, Austin, TX, USA

    Nicholas A. Peppas

  9. Department of Surgery and Perioperative Care, The University of Texas at Austin, Austin, TX, USA

    Nicholas A. Peppas

  10. Department of Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin, Austin, TX, USA

    Nicholas A. Peppas

  11. Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

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Contributions

M.M.B. and R.M.H. conducted the initial literature search and outlined the general manuscript format. M.M.B., R.M.H. and M.E.W. wrote the initial manuscript draft, with contributions from M.J.M., N.A.P. and R.L. All authors reviewed and critically revised previous versions of the manuscript. All authors read and approved the final manuscripts.

Corresponding authors

Correspondence to Michael J. Mitchell, Nicholas A. Peppas or Robert Langer.

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Competing interests

A list of entities with which R.L. is involved, compensated or uncompensated, can be found in the Supplementary information. M.J.M., M.M.B., R.M.H., M.E.W. and N.A.P. declare no competing interests.

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Glossary

Reticuloendothelial system

A system of specialized cells that clear foreign bodies from blood circulation.

PEGylated

Having polyethylene glycol (PEG) polymer chains attached, typically to molecules or macrostructures.

Complement system

A group of distinct plasma proteins that induce inflammation and aid in the clearance of foreign bodies or damaged cells by enhancing antibody and phagocytic cell activity.

Extravasation

The movement or leakage of something (cells, blood, nanoparticles and so on) from a blood vessel into the tissue around it.

Aspect ratios

Numerical comparisons of a nanoparticle’s height and width.

Blood–brain barrier

(BBB). A biological filter made of endothelial cells that restricts the movement of substances from the body to the brain.

Mononuclear phagocytic system

(MPS). The phagocytic cell population of the immune system.

First-pass metabolism

The metabolism of a drug within the liver and enterocytes before the drug reaches the systemic circulation.

Stenosis

The narrowing of a bodily passage (such as a blood vessel).

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Mitchell, M.J., Billingsley, M.M., Haley, R.M. et al. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 20, 101–124 (2021). https://doi.org/10.1038/s41573-020-0090-8

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