Enzyme-responsive nanoparticles for drug release and diagnostics
Abstract
Enzymes are key components of the bionanotechnology toolbox that possess exceptional biorecognition capabilities and outstanding catalytic properties. When combined with the unique physical properties of nanomaterials, the resulting enzyme-responsive nanoparticles can be designed to perform functions efficiently and with high specificity for the triggering stimulus. This powerful concept has been successfully applied to the fabrication of drug delivery schemes where the tissue of interest is targeted via release of cargo triggered by the biocatalytic action of an enzyme. Moreover, the chemical transformation of the carrier by the enzyme can also generate therapeutic molecules, therefore paving the way to design multimodal nanomedicines with synergistic effects. Dysregulation of enzymatic activity has been observed in a number of severe pathological conditions, and this observation is useful not only to program drug delivery in vivo but also to fabricate ultrasensitive sensors for diagnosing these diseases. In this review, several enzyme-responsive nanomaterials such as polymer-based nanoparticles, liposomes, gold nanoparticles and quantum dots are introduced, and the modulation of their physicochemical properties by enzymatic activity emphasized. When known, toxicological issues related to the utilization nanomaterials are highlighted. Key examples of enzyme-responsive nanomaterials for drug delivery and diagnostics are presented, classified by the type of effector biomolecule, including hydrolases such as proteases, lipases and glycosidases, and oxidoreductases.
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Lipid-based nanoparticles (liposomes and solid lipid nanoparticles) have proven biocompatibility and can carry both hydrophilic and hydrophobic drugs, but their clinical application is hindered by rapid clearance via the reticuloendothelial system and stability issues, resulting in some trial failures.
“The most advanced of these are lipid-based NPs (liposomes and SLNs), which have proven biocompatibility and the ability to carry both hydrophilic and hydrophobic drugs. However, their clinical application has been hindered by rapid clearance via the reticuloendothelial system (RES) and stability issues, resulting in some trial failures [9, 100].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [100]
Polymeric nanoparticles offer controlled drug release and modifiable surface properties that enhance targeting and circulation time, but concerns about polymer degradation, toxicity, and inconsistent blood-brain barrier penetration limit their clinical application.
“Polymeric NPs offer the advantages of controlled drug release and modifiable surface properties that enhance targeting and circulation time. However, concerns about polymer degradation, toxicity, and inconsistent BBB penetration limit their clinical application, despite some encouraging preclinical data [100, 155].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [100]
While some trials have demonstrated the safety and feasibility of nanoparticle therapies, many face challenges relating to therapeutic efficacy, pharmacokinetics, and long-term safety, leading to discontinuation of some trials or slow progression.
“While some trials have demonstrated the safety and feasibility of these therapies, many face challenges relating to therapeutic efficacy, pharmacokinetics, and long-term safety. This has led to the discontinuation of some trials or slow progression.”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [100]
Despite promising preclinical results, the clinical translation of nanomedicine-based Alzheimer's disease therapies remains in its early stages, with only a few nanoparticle formulations entering clinical trials, mainly focusing on improving drug delivery across the blood-brain barrier and targeting Aβ or tau pathology.
“Despite promising preclinical results, the clinical translation of nanomedicine-based AD therapies remains in its early stages. Only a few NP formulations have entered clinical trials, with the main focus being on improving drug delivery across the BBB and targeting Aβ or tau pathology.”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [100]
The development of enzyme-responsive nanoparticles for targeted therapy of tumor microenvironment is another effective strategy for nanoparticle intelligence which could release the payload into the desired target.
“The development of enzyme-responsive nanoparticles for targeted therapy of tumor microenvironment is another effective strategy for nanoparticle intelligence which could release the payload into the desired target.143”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [143]
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- Authors
- de la Rica, R., Aili, D., & Stevens, M. M.
- Affiliations
- Nanyang Technological University (SG)
- Imperial College London (GB)
- Corresponding author
- Stevens, Molly M.
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 64
- Issue
- 11
- Pages
- 967-978
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W2162750459
- Cited by
- 765
- References
- 99
- Citations by year
- 2026: 42 · 2025: 57 · 2024: 52 · 2023: 48 · 2022: 60 · 2021: 56 · 2020: 65 · 2019: 68 · 2018: 59 · 2017: 64 · 2016: 53 · 2015: 62 · 2014: 45 · 2013: 24 · 2012: 10
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Funders
- Engineering and Physical Sciences Research Council (EP/J013331/1)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- enzyme-responsive nanoparticles, stimuli-responsive drug delivery, enzyme-responsive drug release, nanomedicine, ultrasensitive biosensor, polymeric nanoparticles, liposomes, gold nanoparticles, quantum dots, proteolytic enzymes, lipase, glycoside hydrolases, oxidative enzymes, nanomaterial toxicity
- MeSH terms
- Diagnostic Imaging, Pharmaceutical Preparations, Hydrolases, Drug Delivery Systems, Nanoparticles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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