Zinc Nanoparticles Attack Cancer Cells on the Metabolic Front

Scientists from Shenyang Pharmaceutical University (China) have published an extensive review of the use of zinc-based nanomaterials in the fight against cancer in Theranostics, revealing their unique mechanisms of action, successful preclinical examples and the main challenges on the way to the clinic.

Why zinc?

Cancer cells metabolize energy in a way that enhances aerobic glycolysis and supports rapid growth. This creates excess reactive oxygen species (ROS) and forces the tumor to build up antioxidant defenses, primarily glutathione (GSH), which allows it to survive oxidative stress.

Zn²⁺ ions can disrupt this adaptation at several levels:

• Block key enzymes of glycolysis (glyceraldehyde-3-phosphate dehydrogenase, lactate dehydrogenase) and enzymes of the Krebs cycle,
• They disrupt the electron transport chain of mitochondria, increasing electron leakage and the generation of superoxide anions,
• Directly increase ROS levels through mitochondrial oxygen reduction reactions and by inhibiting metallothioneins, which normally bind Zn²⁺ and protect the cell from oxidation thno.org.

Types of nanomaterials and their properties

Nanomaterial	Compound	Features of action
ZnO₂	Zinc peroxide	Rapid release of Zn²⁺ and oxygen in acidic tumor environment; gas therapy
ZnO	Zinc oxide	Photocatalytic and photothermal effects under light; generates ROS under laser irradiation
ZIF-8	Imidazolate-Zn	Smart pH-sensitive scaffold for targeted drug delivery; self-releases Zn²⁺
ZnS	Zinc sulfide	Enhances ultrasound (SDT) and photodynamic therapy by promoting local ROS formation

Multimodal approaches

1. Chemotherapy: Zinc nanoparticles enhance the penetration of anti-cancer drugs by damaging membranes and suppressing detox enzymes in the tumor.
2. Photodynamic therapy (PDT): When irradiated, ZnO and ZIF-8 nanoparticles generate ROS, which kills nearby tumor cells without harming healthy tissue.
3. Sonodynamics (SDT): Ultrasound activates ZnS nanoparticles, triggering a ROS cascade and apoptosis.
4. Gas therapy: ZnO₂ decomposes in the tumor microenvironment, releasing oxygen and reducing hypoxia, which increases sensitivity to cytostatics.
5. Immunomodulation: Zn²⁺ activates the STING and MAPK pathway in dendritic cells, enhancing CD8⁺ T-lymphocyte infiltration and creating anti-tumor memory.

Preclinical successes

• In a colon carcinoma model, cisplatin-loaded ZIF-8 completely suppressed tumor growth in mice without systemic toxicity.
• In melanoma, the combination of ZnO-PDT and PD-1 inhibitor resulted in complete regression of primary and distant nodes.
• ZnO₂ nanoparticles in combination with H₂O₂ donors induced a local ROS burst and growth arrest in an estrogen-dependent breast tumor.

Problems and Prospects

1. Safety and biodegradation: It is necessary to minimize the accumulation of ionic zinc in the liver and kidneys, and to ensure controlled degradation of nanoparticles.
2. Standardization of synthesis: uniform protocols and strict control of particle size, shape and surface are necessary for comparability of results.
3. Targeting: PEG-SL or antibody coatings on the surface for targeted tumor delivery and RES bypass.
4. Clinical translation: Most data so far are limited to mouse models; toxicology and pharmacokinetic studies in large animals and phase I trials in humans are required.

The authors of the review note that the success of zinc nanoparticles in preclinical models is largely due to their “multi-armed” action – simultaneous disruption of tumor energy metabolism, increased oxidative stress, and activation of antitumor immunity. Here are some key quotes from the article:

• “Zinc nanoparticles are able to simultaneously attack tumors on three fronts – metabolic, oxidative and immune – making them a unique tool for combination therapy protocols,” said Dr. Zhang, lead author of the review.
• “The main challenge now is to develop biocompatible coatings and targeted delivery systems that will avoid the accumulation of zinc ions in healthy tissues and ensure pinpoint activation in the tumor,” adds Professor Li.
• “We see great potential in combining Zn nanomaterials with immunotherapy: their ability to enhance STING signaling and attract cytotoxic T cells may be a key step towards long-term cancer control,” says study co-author Dr. Wang.

Zinc nanomaterials open a new frontier in oncology, allowing simultaneous disruption of tumor energy metabolism, increase of oxidative stress and stimulation of the immune response. Their diversity and flexibility in combination treatment regimens make them a promising tool for the next generation of anti-cancer therapies.