Cited by 1,361Advanced Drug Delivery SystemsNanoparticle-Based Drug DeliveryRNA Interference and Gene Delivery

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The evolution of commercial drug delivery technologies

Vargason, Ava M., Anselmo, Aaron C., Mitragotri, Samir·2021·Nature Biomedical Engineering

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Abstract

Drug delivery technologies have enabled the development of many pharmaceutical products that improve patient health by enhancing the delivery of a therapeutic to its target site, minimizing off-target accumulation and facilitating patient compliance. As therapeutic modalities expanded beyond small molecules to include nucleic acids, peptides, proteins and antibodies, drug delivery technologies were adapted to address the challenges that emerged. In this Review Article, we discuss seminal approaches that led to the development of successful therapeutic products involving small molecules and macromolecules, identify three drug delivery paradigms that form the basis of contemporary drug delivery and discuss how they have aided the initial clinical successes of each class of therapeutic. We also outline how the paradigms will contribute to the delivery of live-cell therapies.

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Background
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Tay, J. H., Lim, Y. H., Zheng, M., Zhao, Y., Tan, W. S., Xu, C., Ramamurty, U., & Song, J. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.10.016 · Cited by 16
Microbial assistance in nano-carrier development: Innovative strategies in drug delivery
Pandey, T., & Pandey, V. P. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.105607 · Cited by 16
Protein-nanoparticle co-assembly supraparticles for drug delivery: Ultrahigh drug loading and colloidal stability, and instant and complete lysosomal drug release
Xu, Z., Lin, H., Dai, J., Wen, X., Yu, X., Xu, C., & Ruan, G. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124231 · Cited by 16
Nucleus-targeting Oxaplatin(IV) prodrug Amphiphile for enhanced chemotherapy and immunotherapy
Wei, D., Yan, J., Cao, Z., Han, S., & Sun, Y. J. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.07.028 · Cited by 16
Controlled Release of Curcumin and Hypocrellin A from Electrospun Poly( l -Lactic Acid)/Silk Fibroin Nanofibers for Enhanced Cancer Cell Inhibition
Lin, P., Gu, H., Zhuang, X., Wang, F., & Hu, X. (2024) · ACS Applied Bio Materials · doi:10.1021/acsabm.4c00582 · Cited by 16
Novel lipid nanovesicle-loaded dissolving microarray patches for fenretinide in breast cancer chemoprevention
Apolinário, A. C., Naser, Y. A., Volpe‐Zanutto, F., Vora, L. K., Sabri, A. H. B., Li, M., Hutton, A. R. J., McCarthy, H. O., Lopes, L. B., & Donnelly, R. F. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.07.080 · Cited by 16
Facilitated Buccal Insulin Delivery via Hydrophobic Ion-Pairing Approach: In vitro and ex vivo Evaluation
Bashyal, S., Seo, J., Keum, T., Noh, G., Lamichhane, S., Kim, J. H., Kim, C. H., Choi, Y. W., & Lee, S. K. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s318092 · Cited by 16
Venturi-based rapid expansion of supercritical solution (Vent-RESS): synthesis of liposomes for pH-triggered delivery of hydrophilic and lipophilic bioactives
Jash, A., Krueger, A., & Rizvi, S. S. H. (2022) · Green Chemistry · doi:10.1039/d2gc00877g · Cited by 16
Morphology‐controlled precipitation/remodeling of plate and rod‐shaped hydroxyapatite nanoparticles
Latocha, J., Wojasiński, M., Janowska, O., Chojnacka, U., Gierlotka, S., Ciach, T., & Sobieszuk, P. (2022) · AIChE Journal · doi:10.1002/aic.17897 · Cited by 16
Microneedles for anti-aging skincare: Preparation, properties and applications
Awan, K. M., Yu, H., Wang, L., Basit, A., Keshta, B. E., Wang, Y., Malik, M. O., & Uddin, M. A. (2024) · Materials Today Communications · doi:10.1016/j.mtcomm.2024.110740 · Cited by 15
Microfluidic loading of verteporfin into extracellular vesicles for neuroblastoma therapy
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Administration route-commended concise organ-selective mRNA transfection (ACCOST) by cyclic disulfide-primed short polyethylenimine
Ye, R., Ren, Q., Chang, L., Zhang, S., Deng, C., Cao, L., Shi, M., Lou, B., Meng, F., Du, S., et al. (2025) · Nano Today · doi:10.1016/j.nantod.2025.102741 · Cited by 16
Advancing biocompatible metal-organic frameworks in personalized biomedical applications
Yu, Z., Chivu, A., Dai, J., Patra, H. K., Zou, J., & Hu, Z. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.217262 · Cited by 18
Magnetic Microrobots for Drug Delivery: A Review of Fabrication Materials, Structure Designs and Drug Delivery Strategies
Shi, J., Li, Y., Dong, D., Li, J., Wen, T., Tang, Y., Zhang, Q., Pan, F., Yan, L., Wu, D., et al. (2025) · Molecules · doi:10.3390/molecules31010086 · Cited by 16
“The growing demand for precision medicine and personalised treatments in modern healthcare has made efficient, controllable and low-toxicity drug delivery a critical challenge in biomedical research [1–3].”
Covalent organic frameworks as precision nanocarriers for targeted drug delivery: developments, hurdles, and horizons
Irie, T., Das, S. C., & Negishi, Y. (2026) · Nanoscale Horizons · doi:10.1039/d5nh00612k · Cited by 16
Biopharmaceutical nanoclusters: Towards the self-delivery of protein and peptide therapeutics
Danielsen, M., Hempel, C., Andresen, T. L., & Urquhart, A. J. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.04.050 · Cited by 15
Systematic Screening and Therapeutic Evaluation of Glyconanoparticles with Differential Cancer Affinities for Targeted Cancer Therapy
Whang, C., Hong, J., Kim, D., Ryu, H., Jung, W., Son, Y., Keum, H., Kim, J., Shin, H., Moon, E., et al. (2022) · Advanced Materials · doi:10.1002/adma.202203993 · Cited by 15
Natural mussel protein-derived antitumor nanomedicine with tumor-targeted bioadhesion and penetration
He, Y., Wang, J., Wang, S., Yu, K., Zhou, J., Wang, J., Tang, G., Gu, Z., & Bai, H. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101700 · Cited by 15
Reconstructed membrane vesicles from the microalga Dunaliella as a potential drug delivery system
Levak, M., Demir-Yilmaz, I., Formosa‐Dague, C., Vrana, I., Gašparović, B., Horvat, L. L., Butorac, A., Frkanec, R., & DeNardis, N. I. (2022) · Bioelectrochemistry · doi:10.1016/j.bioelechem.2022.108360 · Cited by 15
“The development of drug delivery systems has been extensively researched [1 – 4].”
Background
Bio‐Responsive Macromolecular Drug and Small‐Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement
Li, Y., Liang, X., Shen, C., Deng, K., Zeng, Z., Guo, B., & Xu, X. (2023) · Small · doi:10.1002/smll.202301656 · Cited by 16
Hypoxic regulation of extracellular vesicles: Implications for cancer therapy
Yoo, S., Choi, S., Kim, I., & Kim, I. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.09.034 · Cited by 15
The Importance of Drug Delivery in the Clinical Development and Lifecycle of Drug Products with Examples from Authorised Medicinal Products
Malamatari, M. (2023) · Processes · doi:10.3390/pr11102919 · Cited by 16
“The first category encompasses pharmaceutical compounds with low molecular weight, while the biologics category includes proteins and peptides, antibodies, nucleic acids, and cell therapies [3].”
Background
Redox modulating small molecules having antimalarial efficacy
Pal, C. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115927 · Cited by 15
Photoactivable liposomes for controlled delivery: Recent progress and design considerations
Song, S., Lee, D., Ore, L. C. D., Kwak, S., Kang, L., Kim, H. K., Malmstadt, N., Kim, S. M., & Jeon, T. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215567 · Cited by 16
Co-assembly of polymeric conjugates sensitizes neoadjuvant chemotherapy of triple-negative breast cancer with reduced systemic toxicity
Ren, L. F., Zhang, Q., Wang, W., Chen, X., Li, Z., Gong, Q., Gu, Z., & Luo, K. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.12.026 · Cited by 15
Self-Report Amphiphilic Polymer-Based Drug Delivery System with ROS-Triggered Drug Release for Osteoarthritis Therapy
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Upconverting-photon quenching-mediated perforation influx as an intracellular delivery method using posAuNP@UCNPs nanocomposites for osteoarthritis treatment
Kim, H. J., Cho, H. B., Kim, H.-R., Lee, S., Park, J.-I., & Park, K. (2024) · Nano Convergence · doi:10.1186/s40580-023-00409-y · Cited by 15
An artificial protein modulator reprogramming neuronal protein functions
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“…catalysts can selectively generate favorable intermediates for ef ﬁ cient catalytic reactions 27,28 , their practical biomedical applications are hindered by inherent challenges associated with small molecules 29,30 , such as off-target side effects 31 and untargeted biodistribution 29,32 .”
Advances in Pulmonary Protein Delivery Systems
Zhao, Y., Liu, S., & Lu, X. (2024) · Advanced NanoBiomed Research · doi:10.1002/anbr.202300176 · Cited by 17
Unleashing a Dual‐Warhead Nanomedicine to Precisely Sensitize Immunotherapy for Pancreatic Ductal Adenocarcinoma
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Bioactive peptide relieves glucocorticoid-induced osteoporosis by giant macrocyclic encapsulation
Shang, Y., Zhu, Q., Ding, J., Zhao, L., Zhang, F., Lu, J., Feng, Y., Wang, J., Liu, Z., Kuang, M., et al. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.02.048 · Cited by 15
Advances in Radionuclide-Labeled Biological Carriers for Tumor Imaging and Treatment
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Chitosan-encapsulated lipid-based nanovesicles for therapeutic applications and tissue engineering: A review
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Biomimetic metal-phenolic network-coated elastin-like polypeptide micelles as an immunogenic cell death inducer for orthotopic glioma sonodynamic-chemodynamic-immune therapy
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Unlocking the potential of microalgae-derived therapeutic carriers: Characteristics, types, and nanomedical applications
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“” However, “ Drug delivery technologies have enabled the development of many pharmaceutical products [10].”
Magnetic sustentation as an adsorption characterization technique for paramagnetic metal-organic frameworks
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MIL materials: Synthesis strategies, morphology control, and biomedical application: A critical review
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Authors: Vargason, A. M., Anselmo, A. C., & Mitragotri, S.
Affiliations: University of North Carolina at Chapel Hill (US)
Harvard University (US)
Corresponding author: Mitragotri, Samir
ORCID: Vargason, Ava M.
Anselmo, Aaron C.
Mitragotri, Samir
Venue: Nature Biomedical Engineering
Publisher: Springer Science and Business Media LLC
Published: 2021-04-01
Volume: 5
Issue: 9
Pages: 951-967
ISSN: 2157-846X (ISSN-L)
DOI: 10.1038/s41551-021-00698-w
OpenAlex: W3143156272
Cited by: 1,361
References: 275
Citations by year: 2026: 170 · 2025: 314 · 2024: 366 · 2023: 293 · 2022: 170 · 2021: 48
FWCI: 19.23
Type: journal article
Language: en
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Biomedical Engineering (publishedVersion)
PubMed (publishedVersion)
Funders: National Science Foundation (DGE-1650116)
U.S. Department of Health & Human Services | National Institutes of Health (R35GM137898, 1R01HL143806-01)
United States Department of Defense | Defense Threat Reduction Agency (HDTRA1-15-1-0045)
U.S. Department of Defense (W81XWH-19-2-0011)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords: drug delivery technology, small molecules, macromolecules, nucleic acids, proteins, immunoglobulins, medication adherence
MeSH terms: Pharmaceutical Preparations, Humans, Nucleic Acids, Peptides, Proteins, Drug Delivery Systems

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The evolution of commercial drug delivery technologies

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