Research Progress of Drug Delivery System of Metal-Organic
Framework Materials in Drug Release Mechanisms
Xuechun Wang
Aulin College, Northeast Forestry University, Harbin, Heilongjiang, China
Keywords: Metal-Organic Frameworks (MOFs), Drug Delivery, Controlled Release.
Abstract: Metal-organic framework materials (MOFs) are promising drug carriers due to their high specific surface
area, tunable pore structure, efficient loading and controlled release of drugs and excellent biocompatibility.
In recent years, their application in targeted therapy and controlled release has attracted much attention. In
this paper, we systematically review the preparation of MOFs as drug delivery systems for drug loading and
their drug release mechanisms, focusing on three release strategies: diffusion control, chemical bond breaking
and framework structure change. It was shown that MOFs could realise precise drug release through pH
response, redox triggering and environmental stimuli. MOFs could synergistically deliver antigens and
adjuvants in vaccine carriers to significantly enhance immune response. Despite the significant advantages of
MOFs in targeting and stability, their biodegradability and large-scale production still need to be further
optimised. The study provides insights for designing intelligent drug delivery platforms and promotes MOF
applications in biomedicine.
1 INTRODUCTION
With the increasing demand for precision medicine
and targeted therapies, the design and optimisation of
Drug Delivery Systems (DDS) have become a hot
research topic in biomedical engineering. As an
important research direction in modern medicine, it
aims to enhance the therapeutic effect and reduce the
side effects of drugs by improving drug stability,
targeting, and release efficiency. Traditional delivery
vehicles (e.g., liposomes, polymer microspheres) find
it challenging to meet the demand for precise delivery
in complex pathological environments due to defects
such as low drug loading capacity, poor release
controllability, and insufficient biocompatibility
(Allen&Cullis 2013). In recent years, Metal-Organic
Frameworks (MOFs), highly ordered porous
crystalline materials formed by self-assembling metal
ions or clusters with organic ligands, have a highly
reticular structure (Della et al. 2011). With their ultra-
high specific surface area (up to 7000 m²/g) and
tunable pore size (0.5-10 nm), they are effective in
loading and protecting drug molecules in the field of
drug delivery and enabling controlled drug release by
modulating their pore size and surface properties
(Furukawa et al. 2013). Over the past decade, metal-
organic frameworks (MOFs) have received extensive
attention and intensive research as drug delivery
carriers. Numerous hydrophilic, hydrophobic, and
amphiphilic drug molecules have been successfully
encapsulated, loaded, or attached to the framework
architecture of MOFs. They can be precisely released
at the lesion site for practical therapeutic effects. The
homogeneous pore structure of MOFs can efficiently
incorporate drugs into their cavities, and the large
internal surface area of MOFs significantly enhances
the drug loading capacity. In addition, many MOFs'
weak ligand bonding properties make them
degradable, which provides a strong guarantee for the
smooth release of drugs. As a novel drug delivery
carrier, MOFs can effectively overcome a series of
limitations faced by traditional drug delivery systems,
such as poor drug stability, low water solubility, and
insufficient distribution at the tumour site (Zhao
2018). In drug delivery systems, MOFs can transport
drugs to cells under endogenous (e.g., pH, ions, etc.)
or exogenous stimuli (e.g., light, temperature,
ultrasound, pressure, etc.) to achieve precise and
controlled release of drugs (Li et al. 2022). By
applying this method, changes in the physiological
environment or the application of external stimuli are
regulated to precisely control the release of the drug
at a specific site and time, thus enhancing the drug's
efficacy.
Wang, X.
Research Progress of Drug Delivery System of Metal-Organic Framework Materials in Drug Release Mechanisms.
DOI: 10.5220/0014446100004933
Paper published under CC license (CC BY-NC-ND 4.0)
In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 187-191
ISBN: 978-989-758-789-4
Proceedings Copyright © 2026 by SCITEPRESS – Science and Technology Publications, Lda.
187

The non-toxic effects, targeted and stimulus-
based delivery systems, multiple drug loading
properties, and continuous release have enriched the
applications of MOFs in drug delivery,
biocompatibility, and biodegradability over the last
decade. One of their most important properties, which
scientists continue to explore, is the ability of MOFs
to interact with biological systems (Maranescu&Visa
2022). In addition, MOFs can achieve targeted
delivery through surface modification, further
improving the therapeutic effect of drugs and
demonstrating great potential for application. Despite
the many advantages of MOFs in drug delivery, their
research in drug release mechanisms is still in the
exploratory stage. An in-depth study of the drug
release mechanism of MOFs is of great significance
for optimising their structural design, improving drug
delivery efficiency, and realising clinical
applications.
In this study, the latest research progress of MOFs
in drug release mechanism is reviewed, and three
ways of synthesis of synthetic MOFs drug-carrying
system synthesis and the strategies of their structure
design and performance optimisation under different
release mechanisms are discussed. The article first
introduces MOFs' basic structure and properties, then
elaborates on their diffusion-controlled release,
stimulus-responsive release, and cutting-edge
research results. This article aims to provide a
reference for researchers in related fields and to
promote further research and application of MOFs in
drug delivery—framework structure change release.
2 MOFs DRUG DELIVERY
SYSTEM PREPARATION
MOFs are mainly composed of two parts: metal nodes
and organic ligands. Metal ions or metal clusters are
the backbone of MOFs, and they act as nodes, which
are connected to organic ligands through ligand
bonds. Common metal ions include transition metal
ions (e.g., Zn²⁺, Cu²⁺, Fe²⁺, etc.). Organic ligands
usually contain multiple electron donors, which can
flexibly select the therapeutic needs (targeting,
release mechanism). Their high efficiency and
controllability can assist in forming stable (e.g., a
carboxyl group, amino group, etc.) and coordinate
metal ions between the moiety. Preparation of MOFs
according to the nature of the drugs (hydrophilic and
hydrophobicity) lays the technological foundation.
Conventional synthesis methods for the drug delivery
system include solvothermal and non-solvothermal
methods. The solvothermal method is carried out at
high temperature and pressure and is suitable for
synthesising MOFs with good crystallinity; the non-
solvent thermal process is carried out at ambient
temperature and pressure, which is simple to operate,
but the crystallinity of the product is relatively low.
For example, MIL-53(Al), MOF-5, etc., can be
synthesised by mixing solutions at room temperature.
At the same time, the solvothermal method is suitable
for preparing MOFs with higher crystallinity
(Moharramnejad et al. 2023).
Currently, there are three main ways for MOFs to
load drugs. The first is the two-step encapsulation
method, the second is the one-step encapsulation
method (one-pot method), and the third is the
molecular coordination method in which the drug
molecule is made into a pre-drug coordinated with
metal ions.
2.1 Two-Step Encapsulation Method
The first step is to synthesise the backbone structure
of the MOFs carrier; the second step is to load the
drug by mixing the drug solution with the MOFs and
stirring them at room temperature or heating so that
the drug is loaded into the porous structure of the
MOFs or adsorbed on the surface of the MOFs
through the intermolecular force between the host and
guest molecules or the ion exchange two-step
encapsulation method (Yu et al. 2023). The advantage
of this approach is that MOF synthesis and drug
loading can be optimised independently, and the
crystallinity, pore size, and morphology of MOFs can
be precisely controlled by adjusting the synthesis
conditions (e.g., temperature, pH) to avoid drug
molecules interfering with the nucleation process.
Drug loading conditions (concentration, time,
solvent) can also be optimised independently to
increase the drug loading capacity.
2.2 One-Step Encapsulation (One-Pot
Method)
In the reaction system of the one-step encapsulation
method for synthesising MOFs, metal precursors,
organic ligands, and drug molecules are added
simultaneously to form drug-loaded MOFs through a
self-assembly process or co-crystallization in a single
step. The drug molecules are encapsulated in situ into
the pores of the MOFs (Yu et al. 2023). The advantage
of this method is that no post-processing loading step
is required, and the step of synthesising the MOF
backbone is eliminated, reducing the time and cost;
also, mild synthesis conditions (e.g., room
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temperature, aqueous phase) can avoid drug
degradation.
2.3 Coordination of Drugs as Organic
Ligands
The drug-as-organic-ligand coordination method
involves the coordination of a drug molecule with a
suitable metal ion node so that the drug molecule is
directly involved as a ligand in synthesising a drug-
carrying system. A suitable drug molecule is first
selected to ensure it has a ligand group such as
carboxylic acid, amino, hydroxyl, etc. The drug
molecule must form stable coordination bonds with
metal ions (e.g., Zn²⁺, Fe³⁺, Zr⁴⁺) while maintaining
pharmacological activity. The advantages of this
approach are that the drug acts as a backbone
component, the drug loading is significantly higher
than that of physical adsorption, and the release
kinetics are regulated by the strength of the ligand
bonds to achieve precise drug release.
3 DRUG RELEASE
MECHANISMS IN MOFS DRUG
DELIVERY SYSTEM
Drug release from MOFs drug delivery system is
achieved by breaking the chemical or linkage bonds
of MOFs, causing their structure to disintegrate and
thus releasing the drug. Using the delivery system of
the prepared MOFs drug, it is transported to the
organism to reach a specific location and further
stimulated using the characteristics of its
microenvironment to cause its cleavage to achieve the
targeted treatment and effect of the drug. The
following are three drug-release mechanisms from
MOFs.
3.1 Diffusion-Controlled Releases
Drug molecules slowly diffuse to the external
environment through the pores or surface of MOFs,
and the pore size, pore hydrophilicity, and the
interaction of drug molecules with the pore wall
determine the release rate. The pore size and porosity
of MOFs are the key factors influencing the diffusion
of drugs. Larger pore sizes and higher porosity can
reduce the diffusion resistance of drug molecules in
the pore channels, thus accelerating the drug release
rate. For example, MOFs with larger pore sizes can
allow drug molecules to move more freely in and out
of the pore, similar to a spacious channel, enabling
rapid diffusion of drug molecules into the external
environment. In addition, the interaction between
drug molecules and the pore walls of MOFs can also
affect diffusion.
3.2 Release by Chemical Bond
Breakage
The type of chemical bond formed between MOFs
and drug molecules determines the ease of breaking,
which in turn affects the trigger conditions and rate of
drug release. The primary release mechanism for
chemical bond breaking is ph-responsive release. The
microenvironment of many diseases (e.g. tumours)
has a unique pH, which is usually lower than that of
normal tissues (tumour microenvironments have a pH
of about 6.0-6.5, whereas normal tissues have a pH of
about 7.4). Drug release can be triggered in specific
pH environments by designing pH-sensitive MOFs.
Ligands containing protonatable groups (e.g., amino,
carboxyl, etc.) are selected. In an acidic environment,
protonation of these groups alters the pore structure
of the MOFs, resulting in drug release. pH-responsive
release mainly consists of three mechanisms:
(1) Protonation-driven chemical bond
dissociation. This mechanism contains two modes of
action: one, for MOF materials containing ionisable
functional groups (e.g. imidazole, amino, carboxylic
acid, or pyridine groups), the ligand is deprotonated
under physiologically neutral conditions, and when
the microenvironment is acidified the protonation
effect leads to destabilisation of the metal-ligand
coordination, triggering the decomposition of the
framework structure and the release of the drug; and
the other, based on the acid-sensitive chemical
bonding (e.g. ether, hydrazone or amide bonding)
Secondly, based on acid-sensitive chemical bonds
(e.g., ether, hydrazone or amide bonds), a drug-MOFs
composite system is constructed, and the covalent
bonds are hydrolysed under acidic conditions to
achieve controlled drug release. (2) Charge reversal-
mediated electrostatic release. Due to the change of
pH value in the focal area, the surface charge of the
drug molecule changes, resulting in the original
electrostatic attraction between it and the carrier of
the MOFs changing to repulsion,
which triggers the
drug molecule to detach from the carrier. (3) pH
response regulation of intelligent gating system. By
modifying pH-sensitive functional materials as the
protective layer on the surface of MOFs, the
protective layer undergoes conformational
transformation or degradation in the acidic
microenvironment, thus opening the pore to achieve
drug delivery (Wang et al. 2023).
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The unique pH-responsive release of MOFs,
applied in vaccine carriers, can enable antigens and
adjuvants to be simultaneously and efficiently
delivered to the target cells, thus minimising off-
target release and improving vaccine efficacy.
Compared with soluble antigens, antigens in MOFs
are preferentially taken up, processed, and delivered
by antigen-presenting cells (APCs). Encapsulation of
ovalbumin (OVA) and non-methylated cytosine-
guanine dinucleotide deoxyribonucleic acid (CpG
ODN) in ZIF-8 resulted in pH-responsive release of
OVA-CpG@ZIF-8 nanoparticles, which were able to
deliver OVA and CpG ODN to APCs efficiently. It
induced a stronger immune response than the OVA,
CpG and ZIF-8 mixture alone. Induce a stronger
immune response (Zhang et al. 2021). pH-responsive
release of the MOFs vaccine vector OVA-CpG@ZIF-
8 NPs achieves controlled release of the antigen OVA
through its structural degradation in acidic
environments. This property enables them to
efficiently release antigens in specific organelles in
organisms, enhancing the immunological effect of
vaccines and providing a new strategy for vaccine
delivery and immunotherapy.
3.3 Release of Frame Structure
Changes
The types and ratios of metal ions/clusters and
organic ligands of MOFs, as well as the connection
modes, determine the stability of their framework
structures. By designing these structural parameters
rationally, responsiveness to external stimuli (e.g.,
light, heat, ionic competition, etc.) can induce the
framework's collapse, dissolution, or pore expansion,
thereby modulating the drug release behaviour. For
example, to overcome the problem of premature
release of conventional MOFs in front of the focal
tissue, researchers developed the responsive metal-
organic frameworks (MOFs) described above, which
significantly prolonged the release time of the drug
and improved the therapeutic efficacy. In addition to
the typical stimulus-response, pressure has also been
used to control drug release. Recently, a zirconium-
based MOF constructed from (2E,2E')-3,3'-(2-fluoro-
1,4-phenylene) is acrylic acid (F-H2PDA) and
zirconium clusters and featuring a high drug loading
of the model drug diclofenac sodium (DS) with a drug
loading of 58.80 wt% was developed, which was
attributed to its enhanced polarity and prolonged
organic spacing. The system innovatively uses
pressure to modulate the drug release kinetics,
prolonging the release for 2-8 days to achieve
sustained release. This provides new ideas for
responsive MOF-based drug delivery (Wang&Yang
2017).
There are intracellular differences in the redox
microenvironment, with higher concentrations of
glutathione (GSH) in tumour cells (up to 10 mM) and
lower concentrations of GSH in normal cells (about
two mM). In addition, reactive oxygen species (ROS)
levels are higher in tumour cells. These substances
can trigger a redox reaction, prompting the
dissociation of ligand bonds or a change in the
valence state of the metal centre, leading to the
structural disintegration of the metal-organic
framework carriers, thus enabling the controlled
release of encapsulated drugs. The drug can be
released by designing redox-sensitive materials (e.g.,
MOFs, polymers, etc.) to undergo structural changes
in highly reducing or oxidising environments.
Significant advances have been made in
intelligent delivery systems based on tumour
metabolic profiling in recent years. Glucose oxidase
(GOD) loading is often used to control insulin release
in response to glucose. GOD can convert glucose into
gluconic acid and hydrogen peroxide, thus acidifying
the microenvironment. A decrease in pH can activate
acid-sensitive chemical bond breaking, further
triggering the pH response mechanism for drug
release. The researchers constructed a composite
nano-delivery system based on a metal-organic
framework (ZIF-HA) to achieve tumour
microenvironment-responsive drug release by co-
loading silver nanocubes (AgNCs) and GOD. During
abnormal glycolysis in tumour cells, GOD catalysed
glucose oxidation to generate hydrogen peroxide,
triggering the gradual dissociation of AgNCs into Ag⁺
ions and nanoscale silver particles (AgNPs), which
exerted anti-tumour effects through ion release and
nanoparticle synergy. In vivo experiments showed
that the system significantly inhibited tumour growth
in a hormonal mouse model without causing
significant systemic toxicity, demonstrating excellent
biosafety (Li et al. 2021).
4 CONCLUSION
In this study, we systematically elucidated the core
advantages of MOFs in drug delivery and their
mechanism of action. Through the synergistic effect
of diffusion control, chemical bond breaking, and
dynamic framework remodelling (triple release
mechanism), MOFs can respond to the characteristics
of the tumour microenvironment (e.g., low pH, high
GSH concentration) and significantly enhance drug
targeting and efficacy. These mechanisms provide a
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theoretical basis for applying MOFs in drug delivery
and confirm their advantages in improving
therapeutic efficacy and safety. As a new generation
of intelligent drug carriers, MOFs promote the cross-
fertilisation of nanomedicine disciplines and provide
an innovative solution to the problems of low drug
utilisation and off-target toxicity in clinical
translation.
Although some research results have been
achieved in MOF drug delivery systems, some
limitations remain. Regarding biocompatibility and
degradation, the degradation products and long-term
biological effects of some MOFs materials in vivo are
still unclear, and further research is needed to develop
more biocompatible MOFs materials. Regarding the
precise regulation of drug release, the current release
mechanism research focuses on the single stimulus-
response, and there are fewer studies on the
synergistic reaction of multiple stimuli and the
precise spatial and temporal regulation of drug
release. In the future, we can deeply explore the
multi-modal stimulus-response of the MOFs drug
delivery system to realise the exact release of drugs
in a specific time and space. Regarding clinical
translation, the MOFs drug delivery system and the
actual clinical application are in the laboratory
research stage. It is necessary to strengthen the
cooperation between industry, academia, and research
to promote the clinical translation process to benefit
the patients as soon as possible. Through
interdisciplinary collaboration and technological
innovation, MOFs are expected to achieve
breakthrough applications in cancer therapy, vaccine
development, and regenerative medicine and provide
an efficient and safe delivery platform for precision
medicine, thus enhancing therapeutic efficacy and
improving patient prognosis.
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