The evolution of commercial drug delivery technologies
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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The ultimate goal of smart nanoparticles is that payloads better serve patients: enhance curative effect, reduce toxicity, and prolong survival.
“The ultimate goal of the development of smart nanoparticles is that the payloads can better serve patients: enhance curative effect, reduce toxicity and prolong survival.276”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [276]
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“276 In order to achieve these goals, researchers and medical experts have established various methods to overcome the inherent defects of current drugs.”
BackgroundAdvances in drug delivery systems, challenges and future directions
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“Furthermore, it improves drug solubility, target site accumulation, efficacy, pharmacological activity, pharmacokinetic properties, patient acceptance, and compliance, and reduces drug toxicity [2].”
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Stimuli-Responsive Polymer-Based Nanosystems for Cancer Theranostics.
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Magneto‐Responsive Microneedle Robots for Intestinal Macromolecule Delivery
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Metal–organic frameworks for biological applications
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Recent Applications of PLGA in Drug Delivery Systems
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Advances in Drug Delivery Systems Based on Red Blood Cells and Their Membrane-Derived Nanoparticles
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Tumor Abnormality-Oriented Nanomedicine Design
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Harnessing artificial intelligence for the next generation of 3D printed medicines
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Biomaterials coating for on-demand bacteria delivery: Selective release, adhesion, and detachment
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Let’s talk about sex: Differences in drug therapy in males and females
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“As treatment methods evolve from small molecule chemicals to nucleic acids, peptides, antibodies, and living cells, DDSs are facing numerous obstacles.(16) For example, nanomedicines can transport therapeutic drugs to the target site through enhanced permeability and retention (EPR) effects, but they still accumulate…”
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Bioorthogonal chemistry for prodrug activation in vivo
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Bio-Inspired Nanomaterials for Micro/Nanodevices: A New Era in Biomedical Applications
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CARBON DOTS: Bioimaging and Anticancer Drug Delivery
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Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment
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BackgroundStimulus-responsive self-assembled prodrugs in cancer therapy
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Synthetic Polymers for Drug, Gene, and Vaccine Delivery
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Aptamer-Based Targeted Delivery of Functional Nucleic Acids
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Drug Delivery Systems in Regenerative Medicine: An Updated Review
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“, cancer and invasive fungal infections) [7].”
Electrospun nanofibers for drug delivery applications: Methods and mechanism
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Roll-to-roll, high-resolution 3D printing of shape-specific particles
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Strategic Approaches to Improvise Peptide Drugs as Next Generation Therapeutics
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Novel Drug Delivery Systems: An Important Direction for Drug Innovation Research and Development
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“…approaches, DDS is dedicated to the development of drug delivery systems and devices that can modulate the metabolism, potency, toxicity, immunogenicity, and biorecognition of drugs, thereby enhancing the microenvironment in which the drug operates and facilitating its uptake by the body [1].”
BackgroundRecent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity
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Discovery and delivery strategies for engineered live biotherapeutic products
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Self-citationArtificial Intelligence‐Driven Nanoarchitectonics for Smart Targeted Drug Delivery
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Triplet–triplet annihilation photon upconversion-mediated photochemical reactions
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The emerging role of nanotechnology in plant genetic engineering
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Stimuli-Responsive Nanomedicines for the Treatment of Non-cancer Related Inflammatory Diseases
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Overcoming barriers for intra-articular delivery of disease-modifying osteoarthritis drugs
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“…GI diseases put forward urgent requirements for providing other functions of MagCaps, such as the active targeted delivery in a large spatialarea 42 , site-directed drug releasefor reducing drug dosage and preventing drug side effects 56 , and sampling for biological information in GI tract 6,7 .”
MLCPP 2.0: An Updated Cell-penetrating Peptides and Their Uptake Efficiency Predictor
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Albumin-based delivery systems: Recent advances, challenges, and opportunities
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“Due to the high costs associated with the development of innovative drugs, a very long time to introduce them to the market, and a huge risk of failure in clinical trials, more and more work is focused on the development of new drug-delivery systems [1] based on existing active pharmaceutical ingredients (APIs) with a…”
BackgroundAntibody-based drug delivery systems for cancer therapy: Mechanisms, challenges, and prospects
Chen, Z., Kankala, R. K., Yang, Z., Li, W., Xie, S., Li, H., Chen, A., & Zou, L. (2022) · Theranostics · doi:10.7150/thno.72594 · Cited by 104 · see citing works
“Hence, inhalation powder of human insulin and the anti-IL-13 antigen-binding fragment is being developed and applied clinically [51].”
BackgroundMethodInfluentialSmart hydrogel: A new platform for cancer therapy
Li, G., Fu, Z.-M., Li, H., Wei, R., Guo, J., Wang, H., & Qi, J. (2025) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2025.103470 · Cited by 99 · see citing works
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Exploring the impact of physicochemical properties of liposomal formulations on their in vivo fate
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Sulfobutylether-β-cyclodextrin: A functional biopolymer for drug delivery applications
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Cellular landscaping of cisplatin resistance in cervical cancer
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Regulatory safety evaluation of nanomedical products: key issues to refine
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Cell-Penetrating Peptides (CPPs) as Therapeutic and Diagnostic Agents for Cancer
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Degrader–Antibody Conjugates: Emerging New Modality
Hong, K. B., & An, H. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01791 · Cited by 90 · see citing works
Advancement of Nanofibrous Mats and Common Useful Drug Delivery Applications
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“Despite the promising benefits of these formulations at a preclinical level, only a few colloidal systems are approved for drug delivery in comparison with macro-sized dosage forms [18,19].”
BackgroundBiomaterials-mediated CRISPR/Cas9 delivery: recent challenges and opportunities in gene therapy
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“To increase the effectiveness and speci fi city of CRISPR/Cas9 delivery, a variety of biomaterial-based delivery systems, including nanoparticles, liposomes, and hydrogels, have been investigated (Vargason et al., 2021; Bhattacharjee et al., 2022).”
BackgroundLiposomal Formulations: A Recent Update
Agrawal, S. S., Baliga, V., & Londhe, V. Y. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics17010036 · Cited by 91 · see citing works
“These innovative liposomes are designed to release their contents in response to specific triggers such as changes in pH or the presence of specific enzymes [136].”
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Microrobots for Biomedicine: Unsolved Challenges and Opportunities for Translation
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Bioresponsive drug delivery systems
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Living Leukocyte‐Based Drug Delivery Systems
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Molecular insights of exercise therapy in disease prevention and treatment
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“401 In contrast, other compounds have yielded promising results in animal models but have not found their way into clinical therapy so far.”
ResultFunctionalization of luminescent lanthanide complexes for biomedical applications
Xian, T., Meng, Q. Y., Gao, F., Hu, M., & Wang, X. (2022) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2022.214866 · Cited by 82 · see citing works
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Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles
Wang, L., Quine, S., Frickenstein, A. N., Lee, M., Yang, W., Sheth, V. M., Bourlon, M. D., He, Y., Lyu, S., Garcia‐Contreras, L., et al. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202308446 · Cited by 83 · see citing works
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Advancing drug delivery to articular cartilage: From single to multiple strategies
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“A proper drug delivery carrier retains agent activity, protects agents from clearance, controls agent release, and delivers agents to specific cells or damaged tissues 49 .”
BackgroundAn, Y., Ji, C., Zhang, H., Jiang, Q., Maitz, M. F., Pan, J., Luo, R., & Wang, Y. (2025) · ACS Nano · doi:10.1021/acsnano.4c16280 · Cited by 82 · see citing works
Stimuli‐Responsive Silica Silanol Conjugates: Strategic Nanoarchitectonics in Targeted Drug Delivery
Mohanan, S., Guan, X., Liang, M., Karakoti, A. S., & Vinu, A. (2023) · Small · doi:10.1002/smll.202301113 · Cited by 80 · see citing works
Emerging delivery approaches for targeted pulmonary fibrosis treatment
Diwan, R., Bhatt, H., Beaven, E., & Nurunnabi, M. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115147 · Cited by 78 · see citing works
Biodegradable Materials for Transient Organic Transistors
Stephen, M., Nawaz, A., Lee, S. Y., Sonar, P. M., & Leong, W. L. (2022) · Advanced Functional Materials · doi:10.1002/adfm.202208521 · Cited by 76 · see citing works
Photoresponsive Drug Delivery Systems: Challenges and Progress
Yang, Y., Long, K., Chu, Y., Lu, H., Wang, W., & Zhan, C. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202402975 · Cited by 75 · see citing works
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Constantino, V. R. L., Figueiredo, M. P., Magri, V. R., Eulálio, D., Cunha, V. R. R., Alcântara, A. C. S., & Perotti, G. F. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15020413 · Cited by 73 · see citing works
Wang, Y., Shi, J., Xin, M., Kahkoska, A. R., Wang, J., & Gu, Z. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01230-6 · Cited by 81 · see citing works
“By offering spatiotemporal control over the distribution and release of drugs, advanced drug-delivery systems improve the efficacy of treatments and reduce their side effects 1–5 .”
From Nature‐Sourced Polysaccharide Particles to Advanced Functional Materials
Ma, Y., Morozova, S. M., & Kumacheva, E. (2024) · Advanced Materials · doi:10.1002/adma.202312707 · Cited by 72 · see citing works
Innovative transdermal drug delivery systems: Benefits, challenges, and emerging application
Shah, S. W. A., Li, X., Yuan, H., Shen, H., Quan, S., Pan, G., Ishfaq, M., Shah, A. U., Xie, H., & Shao, J. (2025) · BMEMat · doi:10.1002/bmm2.70001 · Cited by 72 · see citing works
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Delivering living medicines with biomaterials
Harimoto, T., Jung, W., & Mooney, D. J. (2025) · Nature Reviews Materials · doi:10.1038/s41578-024-00766-y · Cited by 72 · see citing works
“Typically, small-molecule drugs (less than ~60 kDa) are metabolized by enzymes such as cytochrome P450 and are rapidly cleared via renal filtration 10,179 .”
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Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury
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Lipid Nanoparticles: A Novel Gene Delivery Technique for Clinical Application
Mashima, R., & Takada, S. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44100341 · Cited by 68 · see citing works
“When extended half-life is desired, 2′-O-methylation and 5′/3′-phosphorothioation are performed [18,21,22] (Figure 2C).”
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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
- Venue
- Nature Biomedical Engineering
- Published
- 2021-04-01
- Volume
- 5
- Issue
- 9
- Pages
- 951-967
- ISSN
- 2157-846X (ISSN-L)
- 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
- 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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