zinc ions

Overview

Zinc ions (Zn²⁺) are divalent cationic forms of the essential trace element zinc, and they play fundamental roles across a vast range of biological processes. As a critical micronutrient, Zn²⁺ serves as a structural cofactor for hundreds of enzymes and transcription factors, participating in DNA synthesis, protein folding, cellular signaling, and immune function. At the molecular level, zinc coordinates with nitrogen, oxygen, and sulfur donor atoms in proteins — particularly through histidine, cysteine, glutamate, and methionine residues — to stabilize tertiary structures and catalytic sites. This coordination chemistry underpins zinc's importance in processes ranging from gene expression regulation to antioxidant defense.

Beyond its homeostatic roles, Zn²⁺ has garnered significant biomedical attention for its capacity to modulate innate immune signaling, induce oxidative stress in aberrant cells, and interfere with tumor metabolism. In the context of cancer biology, elevated or dysregulated intracellular Zn²⁺ concentrations can disrupt mitochondrial function, activate immunogenic cell death (ICD) pathways, and trigger nucleic acid sensing cascades such as the cGAS-STING pathway. These properties have made Zn²⁺ a compelling active component in next-generation nanomedicine platforms, where controlled ion release within the tumor microenvironment (TME) is exploited to achieve synergistic therapeutic effects alongside conventional drugs and immunotherapy.

Focus of Latest Publications

Recent publications have examined zinc ions as a therapeutic payload, structural component, or mechanistic modulator in a range of responsive delivery systems. In cancer-focused studies, Zn2+ was co-delivered with paclitaxel in a ROS-responsive nanoparticle to enhance cGAS-STING signaling, promote dendritic cell maturation, and shift advanced prostate cancer toward a more immunogenic state. A separate hybrid nanogel platform used DNA-mediated chelation of doxorubicin or adsorption of Zn2+ for pH-responsive targeting of sialic acid-overexpressing lung cancers, with the zinc-ion formulation designed for controlled release in the acidic tumor microenvironment. Another nanosystem for breast cancer bone metastasis incorporated Zn2+ interference with MMP2-activatable imaging and photothermal therapy, while a ZIF-8-based carrier released zinc ions together with dihydroartemisinin to suppress malignant pleural effusion and modulate macrophage polarization through the OCT4/NF-κB/M-CSF axis.

Other studies highlighted zinc ions in combination with biomaterials for local antitumor or antimicrobial effects. pH-responsive gelatin microspheres encapsulating zinc sulfide nanoparticles were developed for hepatocellular carcinoma, enabling dual delivery of H2S and Zn2+ after embolization; the reported effects included inhibition of HIF-1α/VEGF signaling, suppression of glycolysis, immune activation, and improved response to anti-PD-1 therapy in a rabbit orthotopic liver tumor model. In tomato bacterial wilt, a double-network hydrogel chelated Zn2+ and released it under acidic conditions together with zhongshengmycin and L-phenylalanine, producing antibacterial activity, enhancing plant growth, activating disease-resistance pathways, and extending disease control in field use.

Beyond delivery applications, one publication focused on the chemistry of zinc-ion binding itself. Methionine-driven covalent chelation by linusorb peptides showed that unoxidized peptides bind Zn2+ more strongly than oxidized forms, with spectroscopic and computational analyses supporting exclusive coordination through methionine sulfur and a covalent character to the S-Zn2+ interaction. Overall, these recent studies portray zinc ions as versatile agents used to trigger release, support targeted delivery, interfere with tumor metabolism or signaling, and contribute to antimicrobial and plant-protective systems.

Key Publications

NEWJun A pH-responsive double network hydrogel for control of tomato bacterial wilt. (Nature communications, 2026, PMID 42285939): "The primary network of carboxylated agarose chelates Zn2+ and loosens under acidic conditions (pH ≤ 5) to release a pesticide (zhongshengmycin) and Zn2+, while the secondary L-phenylalanine (Phe)/ Zn2+ network disassembles to provide additional bioactive components (Phe and Zn2+)."
NEWJun Targeted hybrid nanogels for sialic acid-overexpressing lung cancers: DNA-mediated chelation of doxorubicin and adsorption of zinc ions. (International journal of biological macromolecules, 2026, PMID 42276469): "Designed to deliver a pre-mixed DNA-Doxorubicin (DOX) or DNA-Zinc ion (Zn2+) payload, the APBA-crosslinked NGs leverage the acidic tumor microenvironment to ensure precise and controlled therapeutic release."
May Dihydroartemisinin-Loaded ZIF-8 Nanoparticles Elicit Chemo-Immunotherapy against Malignant Pleural Effusion via Inhibition of OCT4/M-CSF Signaling Pathway. (Molecular pharmaceutics, 2026, PMID 42020944): "Further investigations presented zinc ions and DHA released from the DHA@ZIF-8, which located in lysosome, acted as a direct inhibitor of OCT4."
May Enzyme-Activatable and Tumor-Targeted Nanosystem for Real-Time Imaging and Synergistic Zn2+-Interference Photothermal Therapy of Breast Cancer Bone Metastasis. (Analytical chemistry, 2026, PMID 41999640): "In the acidic tumor microenvironment, Zn2+ release is triggered, and the PDA shell generates near-infrared (NIR) photothermal heating with a conversion efficiency of 50.93%."
May Dual-targeted microspheres reshape the metabolic-immune microenvironment to reverse post-embolization dilemmas in hepatocellular carcinoma. (Cell reports. Medicine, 2026, PMID 41985455): "To address this, we develop pH-responsive gelatin microspheres (GMs) encapsulating zinc sulfide (ZnS) nanoparticles (ZnS-encapsulated gelatin microspheres [ZnS@GMs]) for the dual delivery of hydrogen sulfide (H2S) gas and Zn2+ ions."
May Methionine-driven covalent chelation of Zn2+ by linusorb: a paradigm in hydrophobic cyclic peptide metal binding. (Food chemistry, 2026, PMID 41863922): "This study elucidates the covalent coordination mechanism underlying Zn2+ chelation by linusorbs (LOs) with different redox stages, highlighting the critical role of methionine (Met) residue."
Apr A nanosystem targeting genomic instability and mitochondrial damage to stimulate STING pathway for synergistic immunotherapy for advanced prostate cancer. (Biomaterials, 2026, PMID 41628534): "To address these challenges, we develop a reactive oxygen species (ROS)-responsive nanoparticle, PTX-Zn NP, for the co-delivery of paclitaxel (PTX) and zinc ions (Zn2+)."