Cancer has been at the center of medical research for decades, and despite significant progress, it still remains one of the leading causes of death worldwide. Classic treatments like surgery, chemotherapy, and radiotherapy have saved countless lives, but they also come with serious side effects and limited selectivity.

In recent years, nanomedicine has tried to solve some of these problems by designing smart materials that can find tumors more precisely, deliver drugs more safely, and sometimes diagnose and treat at the same time. One of the most promising families of these materials is metal–organic frameworks (MOFs).

Within this family, a special material called Zeolitic Imidazolate Framework-8 (ZIF-8) has quickly become a favorite. At the nanoscale, ZIF-8 behaves like a tiny, porous sponge that can carry drugs, imaging agents, and even biomolecules such as RNA—then release them in response to the tumor’s own microenvironment.

This article walks through:

• What nanoscale ZIF-8 actually is

• Why it’s so attractive for cancer diagnosis and therapy (“theranostics”)

• How it’s being used in imaging and treatment

• The main challenges holding it back from clinical reality

• And what the future might look like for ZIF-8–based cancer platforms

What Is ZIF-8 and Why Do Researchers Like It?

ZIF-8 is a type of MOF made from zinc ions (Zn²⁺) and an organic linker called 2-methylimidazole. The result is a highly porous, cage-like crystal with a large internal surface area. At the nanoscale (tens to hundreds of nanometers), these crystals can be dispersed as nanoparticles and used in biological systems.

Some key features that make ZIF-8 attractive for cancer applications:

1. Very high porosity and surface area

   • It acts like a sponge that can hold a large amount of drugs, dyes, enzymes, or nucleic acids.

2. pH-responsive degradation

   • ZIF-8 is fairly stable at neutral pH (like blood), but breaks down in acidic conditions, such as those found in tumor tissue, endosomes, and lysosomes.

   • This allows site-specific release of the cargo: more drug in tumor cells, less in healthy tissues.

3. Relatively good biosafety (at controlled doses)

   • Zinc is an essential trace element in the human body.

   • At moderate concentrations, ZIF-8 has shown acceptable biocompatibility in many in vitro and animal studies.

4. Extra “side effects” that can be exploited

   • When ZIF-8 degrades, it releases Zn²⁺, which can:

     • Participate in Fenton-like reactions with hydrogen peroxide (abundant in tumors), generating reactive oxygen species (ROS) that damage cancer cells.

     • Serve as a cofactor for nucleases, helping DNAzymes and some RNases cleave their targets.

     • Influence autophagy, a cellular self-degradation process that can be tuned towards cell death in cancer.

5. Flexible surface modification

   • On its own, ZIF-8 is not very water-dispersible and can aggregate.

   • Its surface is often coated with:

     • PEG (polyethylene glycol) to improve circulation and hide from the immune system,

     • Hyaluronic acid (HA), folic acid (FA), lactobionic acid (LA), or RGD peptides for active targeting to specific receptors on tumor cells,

     • Or even cell membranes (from cancer cells, red blood cells, platelets) for biomimetic “camouflage”.

Put together, these properties make nanoscale ZIF-8 a flexible platform, not just a passive carrier. It can support imaging, drug delivery, and synergistic therapies in the same particle—hence the term “theranostic nanoplatform”.

ZIF-8 in Cancer Imaging

To diagnose and monitor tumors, clinicians rely heavily on imaging techniques such as CT, MRI, and more recently, photoacoustic imaging (PAI) and fluorescence imaging. ZIF-8 on its own is not a strong imaging agent, but it becomes very powerful when it hosts or integrates metals and dyes with contrast or photothermal properties.

1. CT (Computed Tomography)

CT imaging depends on elements with high X-ray absorption (high atomic number), such as gold (Au) or platinum (Pt).

Researchers have:

• Loaded gold nanorods into ZIF-8 and modified the surface with lactobionic acid to target liver cancer cells.

• Built nanoplatforms that include Au and Pt within ZIF-8, resulting in:

  • Strong contrast on CT images

  • Simultaneously, the ability to act as a photothermal agent (for heat-based therapy)

By concentrating these heavy elements inside tumors via ZIF-8, CT images become clearer and more specific.

2. MRI (Magnetic Resonance Imaging)

MRI contrast usually comes from paramagnetic ions like Mn²⁺, Fe³⁺, Gd³⁺, etc.

ZIF-8 can be:

• Doped with Mn²⁺ or coated with MnO₂,

• Combined with iron oxide (Fe₃O₄) or Gd-containing particles.

These nanocomposites show:

• T1-weighted or T2-weighted contrast enhancement in tumors

• pH-responsive behavior: in acidic tumors, ZIF-8 breaks down and releases Mn²⁺, improving local contrast

Some designs even combine MRI with fluorescence imaging, using the intrinsic fluorescence of the imidazole linker or loaded fluorescent nanoparticles. This means clinicians can cross-check tumor position using two different imaging modes.

3. Photoacoustic Imaging (PAI) and Infrared Imaging

PAI sits between optical and ultrasound imaging. A laser pulse heats the material, which expands and generates acoustic waves detected by an ultrasound transducer. For PAI, you need strong near-infrared (NIR) absorbers, often called photothermal agents (PTAs).

ZIF-8-based PAI platforms typically include:

• Gold nanostructures (nanorods, star-shaped nanoparticles)

• Polydopamine (PDA) shells

• Carbon nanomaterials derived from ZIF-8 itself

These structures:

• Convert NIR light into heat and acoustic signals

• Enable deep-tissue imaging with decent resolution

• Often double as photothermal therapy (PTT) agents for heating and killing tumor cells

Some nanoplatforms combine MRI + PAI + CT or FI + MRI, enabling multimodal imaging: better localization, cross-validated diagnosis, and real-time tracking of therapy.

ZIF-8 in Cancer Therapy: From Single Modality to Complex Combinations

ZIF-8 is used not only to see tumors but also to attack them in multiple ways. The review paper organizes these applications into single, dual, triple, and even quadruple therapies. Below we unpack them in a more narrative way.

A. Single-Modality Therapies

1. Immunotherapy

Immunotherapy tries to activate the patient’s immune system to recognize and destroy cancer cells. ZIF-8 can help in several ways:

• Checkpoint inhibitors: antibodies like anti-PD-1 or anti-PD-L1 can be loaded into ZIF-8 for slow, sustained release, which may reduce dosing frequency and improve the activation of T cells.

• Immune adjuvants and DNA motifs (e.g., CpG): these are often negatively charged and poorly taken up by cells. Carriers based on ZIF-8 improve their cellular entry and allow pH-triggered release in endosomes/lysosomes.

• Cancer vaccines: tumor-associated antigens or model antigens (e.g., ovalbumin) can be encapsulated inside ZIF-8. When combined with immunostimulatory DNA and injected, these nano-vaccines:

  • Accumulate in lymph nodes

  • Activate antigen-presenting cells

  • Induce strong T-cell responses and slow tumor growth in animal models

In short, ZIF-8 is emerging as a flexible immunotherapy carrier, capable of delivering antibodies, adjuvants, and antigens in a controlled and targeted way.

2. Starvation Therapy (ST)

Cancer cells consume glucose at very high rates. Starvation therapy tries to cut off this fuel.

A common strategy uses glucose oxidase (GOx), which converts glucose into gluconic acid and hydrogen peroxide. Encapsulating GOx in ZIF-8:

• Protects the enzyme

• Enables its release in the acidic tumor environment

• Depletes glucose locally, “starving” tumor cells

ZIF-8 has also been used to co-encapsulate:

• GOx + horseradish peroxidase (HRP): HRP converts the generated hydrogen peroxide into highly toxic hydroxyl radicals, further damaging tumor cells.

• GOx + lactate transport inhibitors: this double-blocks key energy sources (glucose and lactate) and can also relieve tumor hypoxia by reducing lactate-driven metabolism.

3. Photodynamic Therapy (PDT)

In PDT, a photosensitizer absorbs light and transfers energy to oxygen, generating singlet oxygen (¹O₂) and other ROS that kill cells.

Many classic photosensitizers are hydrophobic and unstable. ZIF-8 helps by:

• Encapsulating molecules like chlorin e6 (Ce6), zinc phthalocyanine (ZnPc), or phycocyanin, protecting them from aggregation and degradation

• Releasing them preferentially in tumor environments

• Sometimes integrating catalase-like components (e.g., MnO₂ or Au nanoparticles) that:

  • Convert endogenous H₂O₂ into oxygen

  • Reduce tumor hypoxia, enhancing PDT efficiency

So ZIF-8 acts as a nanoreactor and shield, enabling more efficient and tumor-selective PDT.

4. Photothermal Therapy (PTT)

In PTT, materials that absorb NIR light convert it into heat and selectively kill cancer cells.

ZIF-8 can host:

• Organic dyes such as indocyanine green (ICG) or cyanine dyes

• Inorganic photothermal agents like bismuth nanodots, gold nanostructures, or carbonized MOF derivatives

Challenges like dye instability, rapid degradation, and poor solubility are mitigated by the ZIF-8 framework. Some designs also add heat-shock protein (HSP) inhibitors, so the tumor cells cannot develop heat resistance, allowing lower temperature PTT (around 43 °C) to be effective.

5. Chemotherapy

Classical chemotherapeutics (DOX, camptothecin, rapamycin, etc.) benefit from ZIF-8’s pH-responsive release:

• Drugs are loaded into ZIF-8 and stay trapped at neutral pH.

• In acidic tumor or intracellular compartments, ZIF-8 breaks down and releases the drug, raising its local concentration.

Interestingly, ZIF-8 itself can influence autophagy—a self-degradation pathway inside cells:

• In some studies, ZIF-8 triggered death-promoting autophagy, which, combined with Zn²⁺ release and ROS generation, made cancer cells more sensitive to chemotherapy (e.g., via rapamycin-loaded ZIF-8 that sensitizes DOX-resistant tumors).

• In other cases, ZIF-8 seemed to induce pro-survival autophagy, which can work against therapy.

This dual behavior is still not fully understood and remains an important research question.

6. Gene Therapy (GT)

Gene therapy uses RNA or DNA-based molecules to silence or edit genes: siRNA, miRNA, DNAzymes, CRISPR/Cas9, RNase A, etc.

ZIF-8 is appealing here because:

• It protects nucleic acids from enzymatic degradation in blood.

• It improves cellular uptake and delivers them into acidic organelles, where ZIF-8 degrades and releases the cargo.

• Released Zn²⁺ helps some nucleic acid enzymes (like DNAzymes or RNase A) function more efficiently.

Examples include:

• RNase A encapsulated in ZIF-8 showing strong anti-proliferative effects in cancer cells.

• ZIF-8 delivering CRISPR/Cas9 elements, with cancer cell membrane coating to provide homotypic targeting (cells take up particles that “look like themselves”).

• DNAzyme + Cu/Zn MOF systems that both synthesize cytotoxic molecules inside cells and cleave oncogene mRNA.

B. Combination Therapies: Dual, Triple, and Quadruple Modes

Cancer is complex, and single-mode treatments often aren’t enough. ZIF-8’s modular nature makes it ideal for combination therapies, where several mechanisms work together.

Dual Therapies

1. Immunotherapy + PTT

   • Nanoplatforms load both a photothermal dye (like IR820 or ICG) and immune stimulants (e.g., imiquimod).

   • PTT ablates the primary tumor and induces immunogenic cell death (ICD), releasing tumor antigens.

   • Immunoadjuvants and checkpoint modulation help turn this into a strong systemic antitumor immune response, sometimes building immune memory that prevents recurrence.

2. Immunotherapy + Gas Therapy

   • CO-generating platforms are an example. Under laser irradiation, a ZIF-8–based system converts CO₂ into CO locally inside the tumor.

   • CO disrupts mitochondrial respiration and promotes ROS production, leading to ICD and stronger immune activation, especially when combined with PD-L1 antibodies.

3. Immunotherapy + Chemotherapy

   • Some ZIF-8 systems carry a chemotherapeutic (like mitoxantrone) plus an epigenetic modulator (like hydralazine).

   • This combination can trigger pyroptosis (a highly inflammatory form of cell death) in tumors and also relieve immunosuppression by affecting myeloid-derived suppressor cells and metabolic checkpoints.

   • The result is both direct tumor killing and improved immune response.

4. Gene Therapy + Chemo-Dynamic Therapy (CDT)

   • CDT uses Fenton or Fenton-like reactions to generate toxic radicals from H₂O₂.

   • ZIF-8 can co-deliver miRNA or siRNA plus metal ions that catalyze ROS production. For example, delivering miR-34a together with Zn²⁺:

     • miR-34a suppresses anti-apoptotic genes.

     • Zn²⁺ participates in Fenton-like ROS generation and lysosomal disruption, enhancing cell death.

5. Gene Therapy + Chemotherapy

   • DNAzyme@Cu/Zn-MOF systems can both generate a chemotherapeutic molecule in situ and cut oncogene mRNA, providing a powerful one–two punch with high specificity.

Triple Therapies

1. Immunotherapy + PTT + Starvation Therapy

   • A typical design: a ZIF-derived porous carbon structure that contains GOx and metal oxides.

   • PTT heats the tumor, promotes GOx activity, and helps ICD; GOx starves the tumor of glucose; ICD and tumor antigen release boost immune responses.

   • This combination has shown strong effects on both primary and distant tumors in animal models.

2. Starvation Therapy + CDT + PDT

   • Here, ZIF-8 carries GOx, a photosensitizer (e.g., Ce6), and components like MnO₂ and PDA.

   • GOx depletes glucose and generates H₂O₂; MnO₂ uses H₂O₂ to produce oxygen and Mn²⁺; Mn²⁺ participates in Fenton-like CDT, and oxygen boosts PDT.

   • PDA and ZIF-8 help maintain stability and contribute to redox and GSH-consuming reactions.

   • The system essentially self-accelerates: each reaction feeds another, improving overall therapeutic efficiency.

3. Gene Therapy + PDT + Chemotherapy

   • Multifunctional nanoparticles can co-load a photosensitizer, a chemotherapeutic drug, and siRNA against HIF-1α, a key transcription factor in hypoxia and drug resistance.

   • By silencing HIF-1α, the system reduces angiogenesis, metastasis, and DNA repair, making tumors more sensitive to PDT and chemo.

   • These designs have shown the ability to overcome multidrug resistance and reduce micrometastases in animal models.

Quadruple Therapy

A striking example is ST + CDT + PTT + Immunotherapy in one ZIF-8–based platform:

• Fe₃O₄ for magnetic targeting + Fenton reaction

• GOx for glucose depletion

• MnO₂ or similar components for oxygen generation and redox modulation

• Photothermal elements for heating

• All integrated into or around ZIF-8

Under a magnetic field and laser irradiation, this kind of complex nanoplatform can:

• Kill primary tumor cells through starvation, ROS, and heat

• Trigger strong ICD and reshape the tumor microenvironment

• Enhance the effect of checkpoint inhibitors such as anti-PD-1

• Inhibit distant metastases as well as the main tumor

Challenges on the Road to the Clinic

Despite all these impressive designs and animal results, ZIF-8-based systems are not yet close to clinical use. Several key challenges remain:

1. Dose-Dependent Toxicity and Long-Term Safety

   • At high concentrations, ZIF-8 can cause significant DNA damage and oxidative stress.

   • Most studies are short-term and in small animals. Long-term biodistribution, clearance, and chronic toxicity data are largely missing.

2. Autophagy Ambiguity

   • ZIF-8 can trigger autophagy, but existing reports disagree on whether this is primarily pro-survival or pro-death.

   • This uncertainty complicates the design of combination therapies, especially with drugs that themselves modulate autophagy.

3. Size, Stability, and Reproducibility

   • Many multi-cargo particles end up larger than 200 nm, which can reduce tumor penetration and cellular uptake.

   • Different synthesis routes, storage conditions, and surface modifications can lead to batch-to-batch variation.

   • For clinical translation, robust, standardized, scalable protocols are required.

4. Complexity of Multi-Cargo Systems

   • Combining photosensitizers, enzymes, drugs, RNAs, and metals in a single particle is elegant, but:

     • Increases manufacturing complexity

     • Makes it harder to predict how each component will behave and interact

     • Raises regulatory hurdles

5. Tumor Heterogeneity and Model Limitations

   • Most work is done in mouse models, often with a single cell line.

   • Human tumors are far more heterogeneous. Patient-derived xenograft models and more diverse tumor types are needed to evaluate the real potential.

6. Cost and Scalability

   • Even if the science works, translation demands cost-effective, high-yield production under GMP conditions.

   • This has not yet been demonstrated for complex ZIF-8 systems.

Outlook: Where ZIF-8 Might Fit in Future Cancer Care

ZIF-8 stands out because it’s more than just a passive carrier:

• Its own degradation products (Zn²⁺) can kill cancer cells preferentially via ROS and metabolic disruption.

• Its pH-sensitive framework provides intrinsic controlled release without extra gatekeepers.

• Its porosity and chemistry enable loading of very different payload types, from small molecules and proteins to nucleic acids and metal ions.

• Its framework can carry imaging agents and therapeutics in the same nanoparticle, enabling true theranostics.

In the short to medium term, the most realistic path may be:

• Simpler, well-defined systems (e.g., single-drug carriers + imaging agent),

• In indications where local delivery or intra-tumoral injections are feasible,

• Combined with rigorous studies on long-term safety, metabolism, and clearance.

Over time, as understanding of its biology deepens, ZIF-8 might play key roles in:

• Smarter immunotherapy platforms (vaccines, checkpoint modulation, ICD amplification)

• Safe delivery of CRISPR/Cas9 and other gene editing tools

• Personalized nanomedicine where diagnosis and therapy are tightly integrated

What is clear from recent research is that ZIF-8 is no longer just a “nice MOF with big pores”. It is evolving into a multifunctional nanoplatform capable of addressing several bottlenecks in cancer diagnosis and treatment—if the remaining safety, complexity, and scalability issues can be overcome.