Engineering precision nanoparticles for drug delivery

doi:10.1038/s41573-020-0090-8

Review

. 2021 Feb;20(2):101-124.

doi: 10.1038/s41573-020-0090-8. Epub 2020 Dec 4.

Engineering precision nanoparticles for drug delivery

Michael J Mitchell^{1

2

3

4

5}, Margaret M Billingsley⁶, Rebecca M Haley⁶, Marissa E Wechsler⁷, Nicholas A Peppas^{8

9

10

11

12}, Robert Langer¹³

Affiliations

¹ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
² Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
³ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁴ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁵ Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁶ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
⁸ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
⁹ Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹⁰ Department of Pediatrics, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹¹ Department of Surgery and Perioperative Care, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹² Department of Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹³ Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.

PMID: 33277608
PMCID: PMC7717100
DOI: 10.1038/s41573-020-0090-8

Review

Engineering precision nanoparticles for drug delivery

Michael J Mitchell et al. Nat Rev Drug Discov. 2021 Feb.

. 2021 Feb;20(2):101-124.

doi: 10.1038/s41573-020-0090-8. Epub 2020 Dec 4.

Authors

Michael J Mitchell^{1

2

3

4

5}, Margaret M Billingsley⁶, Rebecca M Haley⁶, Marissa E Wechsler⁷, Nicholas A Peppas^{8

9

10

11

12}, Robert Langer¹³

Affiliations

¹ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
² Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
³ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁴ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁵ Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
⁶ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
⁸ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
⁹ Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹⁰ Department of Pediatrics, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹¹ Department of Surgery and Perioperative Care, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹² Department of Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin, Austin, TX, USA. peppas@che.utexas.edu.
¹³ Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.

PMID: 33277608
PMCID: PMC7717100
DOI: 10.1038/s41573-020-0090-8

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig. 1. Biological barriers to precision medicine applications.**
Overview highlighting some of the biological barriers that nanoparticles (NPs) can overcome (inner ring) and precision medicine applications that may benefit from NPs (outer ring). As explored in this Review, intelligent NP designs that improve delivery have the potential to enhance the performance of precision medicines and, thus, accelerate their clinical translation. CAR, chimeric antigen receptor; EGFR, epidermal growth factor receptor; EPR, enhanced permeation and retention; gRNA, guide RNA; RNP, ribonucleoprotein.

**Fig. 2. Classes of NPs.**
Each class of nanoparticle (NP) features multiple subclasses, with some of the most common highlighted here. Each class has numerous broad advantages and disadvantages regarding cargo, delivery and patient response.

**Fig. 3. NP characteristics impact distribution.**
Factors such as size, shape, charge and surface coating determine what happens to nanoparticles (NPs) in the circulation, including clearance, and how the NPs interact with local barriers such as the tumour microenvironment or mucus layers. A few general trends are highlighted here: spherical and larger NPs marginate more easily during circulation, whereas rod-shaped NPs extravasate more readily (top left); and uncoated or positively charged NPs are cleared more quickly by macrophages (top right). In terms of local distribution, in general, rod-shaped, neutral and targeted NPs penetrate tumours more readily (bottom left) whereas positively charged, smaller and coated NPs more easily traverse mucosal barriers (bottom right).

**Fig. 4. Common uptake pathways that ultimately determine NP fate within a cell.**
a | Upon interaction with the cell surface, nanoparticles (NPs) — depending on their surface, size, shape and charge — are taken up by various types of endocytosis or pinocytosis via non-specific interactions, such as membrane wrapping, or specific interactions, such as with cell surface receptors. b | Once they have entered the cell, NPs remain trapped within vesicular compartments, or endosomes, that feature various characteristics such as internal or external receptors. To achieve functional delivery, most NPs must escape from these compartments before they acidify. Thus, responsive NPs — such as ionizable NPs that become charged in low-pH environments — aid in endosomal escape and allow for intracellular delivery whereas unresponsive NPs often remain trapped and are destroyed by lysosome acidity and proteolytic enzymes.

**Fig. 5. Commonly engineered NP surface properties that allow for enhanced delivery.**
Surface and material properties, architecture, targeting moieties and responsiveness are all attributes of nanoparticles (NPs) that can be altered in intelligent designs to tailor the platform to a specific application. Different combinations of these four properties allows for seemingly endless permutations of NP features and platforms. PEG, poly(ethylene glycol).

See this image and copyright information in PMC

Cited by

Folate-engineered chitosan nanoparticles: next-generation anticancer nanocarriers.
Kesharwani P, Halwai K, Jha SK, Al Mughram MH, Almujri SS, Almalki WH, Sahebkar A. Kesharwani P, et al. Mol Cancer. 2024 Oct 31;23(1):244. doi: 10.1186/s12943-024-02163-z. Mol Cancer. 2024. PMID: 39482651 Review.
Harnessing extracellular vesicle heterogeneity for diagnostic and therapeutic applications.
Carney RP, Mizenko RR, Bozkurt BT, Lowe N, Henson T, Arizzi A, Wang A, Tan C, George SC. Carney RP, et al. Nat Nanotechnol. 2024 Oct 28. doi: 10.1038/s41565-024-01774-3. Online ahead of print. Nat Nanotechnol. 2024. PMID: 39468355 Review.
Recent Updates on Diverse Nanoparticles and Nanostructures in Therapeutic and Diagnostic Applications with Special Focus on Smart Protein Nanoparticles: A Review.
Muraleedharan A, Acharya S, Kumar R. Muraleedharan A, et al. ACS Omega. 2024 Oct 10;9(42):42613-42629. doi: 10.1021/acsomega.4c05037. eCollection 2024 Oct 22. ACS Omega. 2024. PMID: 39464472 Free PMC article. Review.
Precious Cargo: The Role of Polymeric Nanoparticles in the Delivery of Covalent Drugs.
Weissberger D, Stenzel MH, Hunter L. Weissberger D, et al. Molecules. 2024 Oct 19;29(20):4949. doi: 10.3390/molecules29204949. Molecules. 2024. PMID: 39459317 Free PMC article. Review.
Enhancing Drug Solubility, Bioavailability, and Targeted Therapeutic Applications through Magnetic Nanoparticles.
Zhuo Y, Zhao YG, Zhang Y. Zhuo Y, et al. Molecules. 2024 Oct 13;29(20):4854. doi: 10.3390/molecules29204854. Molecules. 2024. PMID: 39459222 Free PMC article. Review.

See all "Cited by" articles

References

1. The White House Office of the Press Secretary. National Nanotechnology Initiative: leading to the next industrial revolution. White Househttps://clintonwhitehouse4.archives.gov/WH/New/html/20000121_4.html (2000).
1. Kou L, et al. Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types. Front. Pharmacol. 2018;9:1–16. - PMC - PubMed
1. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015;33:941–951. - PMC - PubMed
1. Mitragotri S, et al. Drug delivery research for the future: expanding the nano horizons and beyond. J. Control. Release. 2017;246:183–184. - PubMed
1. Wechsler ME, Vela Ramirez JE, Peppas NA. 110th anniversary: nanoparticle mediated drug delivery for the treatment of Alzheimer’s disease: crossing the blood–brain barrier. Ind. Eng. Chem. Res. 2019;58:15079–15087. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect
- The Lens - Patent Citations
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

[1] The White House Office of the Press Secretary. National Nanotechnology Initiative: leading to the next industrial revolution. White Househttps://clintonwhitehouse4.archives.gov/WH/New/html/20000121_4.html (2000).

[2] The White House Office of the Press Secretary. National Nanotechnology Initiative: leading to the next industrial revolution. White Househttps://clintonwhitehouse4.archives.gov/WH/New/html/20000121_4.html (2000).

[3] Kou L, et al. Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types. Front. Pharmacol. 2018;9:1–16. - PMC - PubMed

[4] Kou L, et al. Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types. Front. Pharmacol. 2018;9:1–16. - PMC - PubMed

[5] Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015;33:941–951. - PMC - PubMed

[6] Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015;33:941–951. - PMC - PubMed

[7] Mitragotri S, et al. Drug delivery research for the future: expanding the nano horizons and beyond. J. Control. Release. 2017;246:183–184. - PubMed

[8] Mitragotri S, et al. Drug delivery research for the future: expanding the nano horizons and beyond. J. Control. Release. 2017;246:183–184. - PubMed

[9] Wechsler ME, Vela Ramirez JE, Peppas NA. 110th anniversary: nanoparticle mediated drug delivery for the treatment of Alzheimer’s disease: crossing the blood–brain barrier. Ind. Eng. Chem. Res. 2019;58:15079–15087. - PMC - PubMed

[10] Wechsler ME, Vela Ramirez JE, Peppas NA. 110th anniversary: nanoparticle mediated drug delivery for the treatment of Alzheimer’s disease: crossing the blood–brain barrier. Ind. Eng. Chem. Res. 2019;58:15079–15087. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Engineering precision nanoparticles for drug delivery

Affiliations

Engineering precision nanoparticles for drug delivery

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials