The platform, designated G@ZnFe-Gel, is built from two humble marine polymers, sodium alginate and the thermoresponsive block copolymer Pluronic F127, into which the researchers embedded nanoparticles they call G@ZnFe-ZIF. These nanoparticles were assembled in two steps. First, zinc ions and 2-methylimidazole formed zeolitic imidazolate framework particles. Then, partial substitution of zinc with ferric iron produced a bimetallic lattice, exploiting the similar ionic radii of tetrahedrally coordinated Fe3+ and Zn2+ to preserve the original MOF topology. Finally, glucose oxidase was immobilized within the porous framework, yielding polyhedral particles roughly 116 nanometers across whose roughened surfaces and retained X-ray diffraction signatures confirmed that neither enzyme loading nor iron substitution had disrupted the crystalline scaffold.

The catalytic logic of the nanozyme is a cascade designed to weaponize the tumor’s own metabolism. Glucose oxidase consumes tumor glucose and generates hydrogen peroxide, simultaneously starving cancer cells of their primary energy source and supplying the substrate for iron-catalyzed Fenton-like reactions that convert hydrogen peroxide into highly destructive hydroxyl radicals. Chromogenic assays using tetramethylbenzidine demonstrated that only the complete system, nanozyme plus glucose, produced the strong colorimetric signal of hydroxyl radical generation, while control formulations lacking either the enzyme or the metals remained inert. Glucose consumption assays further showed that the immobilized enzyme retained its activity and even displayed improved stability during prolonged incubation in serum-containing conditions, a critical property for a depot intended to function inside a living tumor.

Getting such a depot to stay put within the dense pancreatic stroma is the second half of the engineering challenge. The hydrogel precursor is a free-flowing liquid at four degrees Celsius, allowing smooth extrusion through a conventional syringe, but once injected it encounters body temperature and the calcium-rich tumor microenvironment. Pluronic F127 micellizes above thirty degrees Celsius, alginate crosslinks ionically with calcium, and the embedded bimetallic nanozymes act as multivalent structural bridging nodes that further densify the network. Together these three mechanisms, thermal gelation, ionic crosslinking, and nanozyme reinforcement, shortened gelation time to approximately one minute. Scanning electron microscopy revealed that the nanozyme-loaded gel possessed a markedly more compact porous architecture than the plain polymer gel, and Fourier-transform infrared spectroscopy documented shifts in hydrogen bonding, methylene stretching, and carboxylate bands consistent with metal coordination between the framework ions and the polymer matrix.

Rheological testing underscored the mechanical payoff of this design. The storage modulus of G@ZnFe-Gel exceeded that of all comparator gels, and the material recovered its viscoelastic properties within seconds after repeated cycles of high-strain disruption, demonstrating a self-healing capability well suited to the mechanical stresses of living tissue. In rats, a fluorescently labeled formulation remained in place with gradually declining signal over seven days, indicating stable local retention followed by progressive, controlled degradation. This profile is exactly what an intratumoral depot requires: long enough residence to sustain therapeutic release, but no permanent burden on the tissue.

In pancreatic cancer cells, the formulation proved devastating. Hemolysis assays showed all gel formulations caused less than five percent red blood cell destruction, meeting the ISO 10993 blood compatibility standard, while the full system exhibited the strongest concentration-dependent killing of PAN02 pancreatic cancer cells. Fluorescent probes revealed that G@ZnFe-Gel drove the highest intracellular reactive oxygen species levels of any formulation, and flow cytometry showed it pushed roughly 55 percent of treated cells into apoptosis, with viable cells falling to about 40 percent. Western blot analysis then traced the cell death program to ferroptosis: expression of the lipid peroxide-detoxifying enzyme GPX4 and the iron storage protein FTH1 both fell sharply, while the compensatory antioxidant axis involving NRF2, KEAP1, and the cystine transporter xCT ramped up in a futile attempt to restore redox balance. The oxidative pressure ultimately overwhelmed these defenses, enforcing irreversible lipid peroxidation and cell death.

The immunological payoff came next. Ferroptosis releases damage-associated molecular patterns, potentially including mitochondrial DNA, which can flood the cytosol and activate the cGAS-STING innate immune sensor. In treated cells, the phosphorylated forms of STING, TBK1, and IRF3 rose markedly even as total protein levels dipped, a signature of robust pathway activation. Phosphorylated IRF3 translocated into the nuclei of macrophages, and interferon-beta transcripts surged. Pharmacological rescue experiments sealed the causal chain: blocking ferroptosis with ferrostatin-1 dampened TBK1 phosphorylation and reduced interferon-stimulated gene expression, while inhibiting cGAS with RU.521 partially restored cell viability, confirming that the cell death program and the immune signaling cascade are functionally coupled. Interleukin-6 mRNA also climbed, signaling a broader pro-inflammatory shift.

RNA sequencing of treated tumor cells provided a systems-level confirmation of the mechanism. Differentially expressed genes were prominently enriched in ferroptosis, apoptosis, cGAS-STING signaling, and cytosolic DNA sensing pathways, alongside glutathione metabolism reflecting the collapse of antioxidant defenses. Gene set enrichment analysis additionally flagged TNF signaling and T-cell receptor signaling, hinting that the treatment primes the tumor for immune engagement. Crucially, pathways governing endoplasmic reticulum stress-related survival and metabolic adaptation were downregulated, suggesting the therapy disables the buffering programs pancreatic cancer cells rely on to survive in fibrotic, nutrient-starved surroundings, pushing them from a reversible adaptive state into irreversible programmed death.

In mice bearing subcutaneous pancreatic tumors, the results were striking. Tumors treated with the full system nearly stopped growing over a twenty-day course, and endpoint tumor weights fell roughly forty percent below those of the iron-only gel group, with some specimens fragmenting or showing extensive necrosis. Ki67 staining revealed almost no proliferating cells, TUNEL assays showed maximal cell death, and immunofluorescence painted a picture of a tumor microenvironment transformed: intense oxidative stress, suppressed GPX4, elevated STING and interferon-beta, strong calreticulin exposure and HMGB1 release marking immunogenic cell death, macrophages repolarized from the immunosuppressive M2 phenotype toward tumoricidal M1, and a flood of infiltrating CD8+ cytotoxic and CD4+ helper T cells producing interferon-gamma at roughly sixty times control levels. Circulating T and B cells also expanded, indicating that local treatment rippled outward into systemic adaptive immunity.

Safety data supported the platform’s promise. Treated mice maintained stable body weight, liver enzymes ALT and AST and kidney markers creatinine and blood urea nitrogen stayed within normal ranges, and histology of the heart, liver, spleen, lungs, and kidneys showed no pathological damage. The authors caution that long-term zinc and iron biodistribution, clearance, immune memory, and efficacy in more representative pancreatic cancer models remain to be established before clinical translation. Even so, the study demonstrates a compelling materials-design principle: by letting the tumor’s own acidity, calcium, and glucose trigger gelation, starvation, and radical generation in place, a seaweed-derived hydrogel can convert a cold, stroma-shielded malignancy into an inflamed target of its own immune destruction.

Subject of Research: A microenvironment-responsive injectable marine polysaccharide hydrogel with bimetallic MOF nanozymes for ferroptosis-mediated cGAS-STING activation in pancreatic cancer immunotherapy

Article Title: Microenvironment-responsive injectable marine polysaccharide hydrogel empowered by bimetallic MOF nanozymes for in situ pancreatic cancer immunotherapy via ferroptosis-mediated cGAS-STING activation

Article References: Zhan, Y., Shi, C., Dong, J., Zhao, S., Gao, X., Li, J., Chen, X., & Li, Y. (2026). Microenvironment-responsive injectable marine polysaccharide hydrogel empowered by bimetallic MOF nanozymes for in situ pancreatic cancer immunotherapy via ferroptosis-mediated cGAS-STING activation. Materials Today Bio, 41, Article 103735. https://doi.org/10.1016/j.mtbio.2026.103735

Image Credits: AI Generated

DOI: Not provided

Keywords: pancreatic cancer, hydrogel, nanozyme, metal-organic framework, ferroptosis, cGAS-STING, immunotherapy, glucose oxidase, sodium alginate, tumor microenvironment, reactive oxygen species, immunogenic cell death