Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

Thomas Anchordoquy¹, Natalie Artzi^{2

3

4}, Irina V Balyasnikova⁵, Yechezkel Barenholz⁶, Ninh M La-Beck⁷, Jacob S Brenner⁸, Warren C W Chan^{9

10}, Paolo Decuzzi¹¹, Agata A Exner¹², Alberto Gabizon¹³, Biana Godin^{14

15

16

17}, Samuel K Lai¹⁸, Twan Lammers¹⁹, Michael J Mitchell^{20

21}, S Moein Moghimi^{22

23

24}, Vladimir R Muzykantov²⁵, Dan Peer^{26

27

28

29}, Juliane Nguyen¹⁸, Rachela Popovtzer³⁰, Madison Ricco¹, Natalie J Serkova³¹, Ravi Singh^{32

33}, Avi Schroeder³⁴, Anna A Schwendeman³⁵, Joelle P Straehla^{36

37}, Tambet Teesalu³⁸, Scott Tilden¹, Dmitri Simberg¹

Affiliations

¹ Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, the University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
² Brigham and Woman's Hospital, Department of Medicine, Division of Engineering in Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02215, United States.
⁴ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02215, United States.
⁵ Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
⁶ Membrane and Liposome Research Lab, IMRIC, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel.
⁷ Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, Texas 79601, United States.
⁸ Departments of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
⁹ Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
¹⁰ Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
¹¹ Laboratory of Nanotechnology for Precision Medicine, Italian Institute of Technology, 16163 Genova, Italy.
¹² Departments of Radiology and Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
¹³ The Helmsley Cancer Center, Shaare Zedek Medical Center and The Hebrew University of Jerusalem-Faculty of Medicine, Jerusalem, 9103102, Israel.
¹⁴ Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, United States.
¹⁵ Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, Texas 77030, United States.
¹⁶ Department of Obstetrics and Gynecology, Weill Cornell Medicine College (WCMC), New York, New York 10065, United States.
¹⁷ Department of Biomedical Engineering, Texas A&M, College Station, Texas 7784,3 United States.
¹⁸ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, United States.
¹⁹ Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Center for Biohybrid Medical Systems, University Hospital RWTH Aachen, 52074 Aachen, Germany.
²⁰ Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²¹ Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²² School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
²³ Translational and Clinical Research Institute, Faculty of Health and Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K.
²⁴ Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, United States.
²⁵ Department of Systems Pharmacology and Translational Therapeutics, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²⁶ Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁷ Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁸ Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁹ Cancer Biology Research Center, Tel Aviv University, Tel Aviv, 69978, Israel.
³⁰ Faculty of Engineering and the Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, 5290002 Ramat Gan, Israel.
³¹ Department of Radiology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado 80045, United States.
³² Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, United States.
³³ Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina 27101, United States.
³⁴ Department of Chemical Engineering, Technion, Israel Institute of Technology, Haifa 32000, Israel.
³⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48108; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48108, United States.
³⁶ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts 02115 United States.
³⁷ Koch Institute for Integrative Cancer Research at MIT, Cambridge Massachusetts 02139 United States.
³⁸ Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.

PMID: 38767983
PMCID: PMC11214758
DOI: 10.1021/acsnano.4c00182

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

Thomas Anchordoquy et al. ACS Nano. 2024.

. 2024 Jun 4;18(22):13983-13999.

doi: 10.1021/acsnano.4c00182. Epub 2024 May 20.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, the University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
² Brigham and Woman's Hospital, Department of Medicine, Division of Engineering in Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02215, United States.
⁴ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02215, United States.
⁵ Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
⁶ Membrane and Liposome Research Lab, IMRIC, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel.
⁷ Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, Texas 79601, United States.
⁸ Departments of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
⁹ Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
¹⁰ Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
¹¹ Laboratory of Nanotechnology for Precision Medicine, Italian Institute of Technology, 16163 Genova, Italy.
¹² Departments of Radiology and Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
¹³ The Helmsley Cancer Center, Shaare Zedek Medical Center and The Hebrew University of Jerusalem-Faculty of Medicine, Jerusalem, 9103102, Israel.
¹⁴ Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, United States.
¹⁵ Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, Texas 77030, United States.
¹⁶ Department of Obstetrics and Gynecology, Weill Cornell Medicine College (WCMC), New York, New York 10065, United States.
¹⁷ Department of Biomedical Engineering, Texas A&M, College Station, Texas 7784,3 United States.
¹⁸ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, United States.
¹⁹ Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Center for Biohybrid Medical Systems, University Hospital RWTH Aachen, 52074 Aachen, Germany.
²⁰ Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²¹ Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²² School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
²³ Translational and Clinical Research Institute, Faculty of Health and Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K.
²⁴ Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, United States.
²⁵ Department of Systems Pharmacology and Translational Therapeutics, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
²⁶ Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁷ Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁸ Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, 69978, Israel.
²⁹ Cancer Biology Research Center, Tel Aviv University, Tel Aviv, 69978, Israel.
³⁰ Faculty of Engineering and the Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, 5290002 Ramat Gan, Israel.
³¹ Department of Radiology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado 80045, United States.
³² Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, United States.
³³ Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina 27101, United States.
³⁴ Department of Chemical Engineering, Technion, Israel Institute of Technology, Haifa 32000, Israel.
³⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48108; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48108, United States.
³⁶ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts 02115 United States.
³⁷ Koch Institute for Integrative Cancer Research at MIT, Cambridge Massachusetts 02139 United States.
³⁸ Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.

PMID: 38767983
PMCID: PMC11214758
DOI: 10.1021/acsnano.4c00182

Abstract

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic. At the recent conference workshop "Mechanisms and Barriers in Nanomedicine" in May 2023 in Colorado, U.S.A., leading experts discussed the formulation, physiological, immunological, regulatory, clinical, and educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, and students to trigger ideas and concepts to move the field forward.

Keywords: barriers; complement; delivery; formulation; inflammation; mRNA; nanomedicine; translation; tumor.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): D.P. receives licensing fees (to patents on which he was an inventor) from, invested in, consults (or on scientific advisory boards or boards of directors), or Founder of, or conducts sponsored research at TAU for the following entities: ART Biosciences, BioNtech SE, Earli Inc., Kernal Biologics, Geneditor Biologics Inc., Newphase Ltd., NeoVac Ltd., RiboX Therapeutics, Roche, SirTLabs Corporation, Teva Pharmaceuticals Inc.

Figures

**Figure 1.**
Gartner Hype Cycle. Reprinted with permission from ref 3.

**Figure 2.**
Our view of the progress in overcoming the formulation barrier.

**Figure 3.**
Our view of the progress in overcoming the immunological/physiological barrier

**Figure 4.**
Targeted complement regulators (orange) are natural inhibitors that bind to initial complement depositions (green) on nanoparticle surfaces (blue) in blood and protect them from full-scale complement attack. Artistic illustration by Ella Mary Studio.

**Figure 5.**
Nanoparticle movement (extravasation) from blood to tissue compartments may include a) passive diffusion, b) immune cell uptake and hitchhiking, c) transcytosis, for example, via vesiculo-vacuolar organelles (VVOs) or endocytosis. Nanoparticles can extravasate intact or as individual components after degradation/disintegration in blood and endothelial/immune cells.

**Figure 6.**
Our view of the progress in overcoming the clinical/regulatory barriers.

See this image and copyright information in PMC

References

1. Allen TM; Cullis PR Liposomal Drug Delivery Systems: From Concept to Clinical Applications. Adv. Drug Deliv Rev. 2013, 65, 36–48. - PubMed
1. Maeda H; Fang J; Inutsuka T; Kitamoto Y Vascular Permeability Enhancement in Solid Tumor: Various Factors, Mechanisms Involved and Its Implications. Int. Immunopharmacol 2003, 3, 319–28. - PubMed
1. Couvreur P Nanomedicine: From Where Are We Coming and Where Are We Going? J. Controlled Release 2019, 311–312, 319–321. - PubMed
1. Stiepel RT; Duggan E; Batty CJ; Ainslie KM Micro and Nanotechnologies: The Little Formulations That Could. Bioeng Transl Med. 2023, 8, No. e10421. - PMC - PubMed
1. Anselmo AC; Mitragotri S Nanoparticles in the Clinic: An Update Post Covid-19 Vaccines. Bioeng Transl Med. 2021, 6, No. e10246. - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

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

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

Affiliations

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources