Zinc-Locked Herbal Hydrogel Attacks Tumors and Their Blood Supply at Once

A new injectable hydrogel that combines a plant-derived anticancer compound, citrus pectin, and zinc ions has shown striking antitumor activity in mice, and its designers say the material is not merely a drug carrier but an active therapeutic agent in its own right. The system, described in the journal Materials Today Bio, was developed by Kai Li, Qili Sun, and colleagues at institutions affiliated with the Guangdong Provincial Key Laboratory of Advanced Biomaterials. Their formulation, called Rhein/Pectin@Zn, is built on a simple but powerful piece of coordination chemistry: metal-ligand bonds that lock the gel network together while simultaneously delivering two biologically active payloads directly into the tumor.

The motivation behind the work is a persistent gap in solid tumor management. Surgery, radiotherapy, and chemotherapy all leave something to be desired: primary lesions are sometimes incompletely eradicated, off-target toxicity harms healthy tissue, and tumors acquire resistance to systemic drugs. Injectable hydrogels have attracted attention as local drug depots because they can be administered minimally invasively, conform to irregular tissue cavities, and release their cargo slowly over time. Yet most existing hydrogels are passive. They hold a drug and let it diffuse out, but they contribute no intrinsic bioactivity and do nothing to remodel the pathological environment that sustains the tumor.

The Chinese team’s answer was to make every component of the gel do double duty. The first active ingredient is rhein, a natural anthraquinone found in traditional medicinal plants. Rhein has a planar, three-ringed structure that allows it to self-assemble through pi-pi stacking under alkaline conditions, and it carries a peri-hydroxy ketone motif that chelates divalent metal ions. That makes it an ideal structural building block for a coordination network. Crucially, rhein also has documented antiproliferative and antiangiogenic properties, so the molecule that stiffens the gel is the same molecule that attacks the tumor.

The second key player is zinc. Zinc ions are famous in polysaccharide chemistry for forming the canonical egg-box crosslinks with carboxyl groups on pectin chains, the same motif that gives jams their set. But zinc is more than a molecular staple. Disrupting zinc homeostasis can induce tumor cell apoptosis and inhibit the activation of endothelial cells that line new blood vessels. Free zinc ions, however, are cleared rapidly from the body and cause dose-limiting toxicity, which is precisely why a localized depot that retains and slowly releases the metal is attractive. In the Rhein/Pectin@Zn system, zinc serves as both crosslinker and drug.

Building the material required careful molecular characterization of the pectin scaffold. Using high-performance liquid chromatography, the researchers identified glucose, galacturonic acid, galactose, arabinose, and rhamnose as the principal monosaccharides in their citrus-peel pectin, with gel permeation chromatography yielding an apparent molecular weight of 2.76 times ten to the fifth and a broad polydispersity index of 4.29. Methylation analysis followed by gas chromatography-mass spectrometry, together with nuclear magnetic resonance spectroscopy, confirmed the expected pectic framework, including 1,4-linked galacturonic-acid-derived residues that provide the carboxyl groups needed for zinc coordination.

To make the hydrogel, the team dissolved rhein in mildly alkaline HEPES buffer at 65 degrees Celsius, mixed in pectin, and then induced crosslinking with zinc acetate. Scanning electron microscopy revealed a porous internal architecture that became denser and more organized as rhein content increased, consistent with additional intermolecular interactions beyond simple ionic crosslinking. Energy-dispersive X-ray spectroscopy confirmed zinc throughout the network and showed that zinc content rose with rhein loading, indicating that rhein contributes extra coordination sites. X-ray diffraction showed the loss of the starting materials’ crystalline peaks, while Fourier transform infrared spectroscopy revealed changes in hydroxyl and carbonyl bands consistent with hydrogen bonding and metal coordination rather than chemical degradation.

Rheological testing confirmed that the gels behave as predominantly elastic solids, with the storage modulus exceeding the loss modulus over time and both moduli increasing as rhein content rose. The material also showed a clear linear viscoelastic region followed by yielding at high strain, and its viscosity dropped sharply under shear. Swelling decreased with increasing rhein content, reflecting the denser network, and release experiments demonstrated sustained rhein liberation that was faster at pH 6.5 than at pH 7.4, a pH-responsive behavior well suited to the acidic tumor milieu. The authors are careful to note, however, that these measurements were made on gels crosslinked under standardized laboratory conditions, and that the depot formed in situ inside a tumor by dual-syringe mixing may differ quantitatively in crosslinking density and release behavior.

The biological results were the heart of the study. In vitro, extracts of the rhein-containing gel reduced the viability of B16 melanoma cells in a concentration-dependent manner and also suppressed human umbilical vein endothelial cells, with a fitted IC50 of 18.28 micrograms per milliliter for B16 cells compared with 360.0 micrograms per milliliter for the zinc-pectin carrier alone. Flow cytometry showed an increased apoptotic fraction, an elevated Bax/Bcl2 mRNA ratio, and accumulation of cells in the G2/M phase of the cell cycle, while scratch assays indicated inhibited tumor cell migration. In endothelial cells, the gel reduced transcripts for pro-angiogenic factors including VEGF, EGF, HGF, and EGFL6, along with CD31 and VEGF protein signals. Hemolysis testing placed all formulations below the 2 percent nonhemolytic threshold, and the gel reduced inflammatory transcripts in stimulated macrophages, a preliminary safety signal.

In vivo, the team used a dual-syringe system connected through a three-way stopcock to co-inject the liquid rhein-pectin precursor and the zinc solution directly into subcutaneous B16 melanomas in mice, allowing gelation to occur only at the target site. Tumors treated on days 0, 2, and 4 with the full formulation were markedly smaller at the endpoint than controls, with the zinc-pectin carrier producing only partial inhibition. Histology showed more extensive tissue damage, reduced Ki-67 proliferation staining, increased TUNEL apoptosis, a higher BAX/BCL-2 ratio, and reduced CD31 vascular staining in treated tumors, while major organs showed no overt abnormalities.

Transcriptomic profiling of treated tumors pointed to a coherent mechanism the authors describe as an arrest-and-death strategy. Pathway enrichment highlighted cell-cycle regulation and p53-associated apoptosis. The gene Ccnb1, which encodes Cyclin B1, a critical regulatory subunit of the M-phase promoting factor, was downregulated, inactivating the complex that initiates mitosis and trapping cells at the G2/M checkpoint. Simultaneously, Bbc3, which encodes the p53 target PUMA, was upregulated; this BH3-only protein antagonizes anti-apoptotic members of the BCL-2 family and activates the mitochondrial death pathway in the arrested cells. The authors caution that the current evidence does not establish formal synergy between components, equivalence between laboratory and in situ gel states, or comprehensive systemic safety, and they call for component-resolved controls and residual-tumor models in future work. Even with those caveats, the study offers a compelling proof of concept: a single injection of flowable liquids that gels on demand, releases a herbal drug and a therapeutic metal for days, starves the tumor of its vascular support, and shuts down cell division from the inside.

Subject of Research: A coordination-strengthened rhein/pectin/zinc dual-network hydrogel for local antitumor and antiangiogenic therapy

Article Title: Coordination-strengthened Rhein/Pectin@Zn dual-network hydrogel for local antitumor therapy

Article References: Li, K., Sun, Q., Chen, J., Wang, Y., Zhao, E., Cao, S., Xie, C., & Tang, B. (2026). Coordination-strengthened Rhein/Pectin@Zn dual-network hydrogel for local antitumor therapy. Materials Today Bio, 41, Article 103733. https://doi.org/10.1016/j.mtbio.2026.103733

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103733

Keywords: hydrogel, rhein, pectin, zinc ions, coordination chemistry, drug delivery, melanoma, angiogenesis, apoptosis, G2/M arrest, tumor microenvironment, local cancer therapy