The new platform, described in the journal Materials Today Bio, is built from hyaluronic acid, a naturally occurring polysaccharide already familiar from cosmetic and biomedical applications. The key insight lies in the chemistry of crosslinking. Hyaluronic acid, with its abundant carboxyl groups, readily coordinates with multivalent cations such as calcium ions, forming a three-dimensional hydrogel network reinforced by hydrogen bonds in humid conditions. But when the gel encounters tissue fluid rich in monovalent sodium and potassium ions, ligand exchange displaces the pre-chelated calcium and the network rapidly falls apart. This dynamic, switchable coordination network gives the microneedles a rare combination of properties: enough mechanical strength to pierce the oral epithelium when dry, and near-instant disintegration once exposed to the salty microenvironment of ulcerated tissue.

The design inspiration came from nematocysts, the microscopic harpoon-like organelles that jellyfish use to discharge venom in response to osmotic pressure. To mimic this triggered-release strategy, the researchers first constructed drug-loaded nanofibers from glycyrrhizic acid, a natural saponin that self-assembles into long-range ordered structures with internal hydrophobic domains. Using a low-frequency acoustic resonance technique operating at 55 hertz, they co-assembled glycyrrhizic acid with two complementary plant-derived therapeutics: baicalein, a flavonoid that disrupts bacterial cell walls and inhibits bacterial DNA synthesis, and astaxanthin, a potent carotenoid antioxidant that scavenges reactive oxygen species and promotes tissue repair. The resulting nanofibers measured just 3 to 4 nanometers in diameter but stretched up to 5 micrometers in length, an extraordinary aspect ratio of 1250, with surface zeta potentials exceeding 40 millivolts that keep the suspensions physically stable.

Encapsulation within the nanofibers solved one of the most stubborn problems in phytochemical medicine: poor water solubility. Free baicalein and astaxanthin barely dissolve in aqueous media, but once loaded into the glycyrrhizic acid fibers their apparent solubilities rose to 775.50 and 95.16 micrograms per milliliter, corresponding to enhancements of 127.5-fold and 213.7-fold respectively. Because the nanofibers carry abundant surface carboxyl groups, they behave like anionic polymers and can themselves participate in calcium-mediated gelation, becoming woven into the hyaluronic acid matrix rather than merely suspended within it. When calcium chloride solution was added, a stable, self-healing gel formed within one minute, confirmed by scanning electron microscopy and rheological testing that revealed the characteristic thixotropic behavior of an electrostatically crosslinked network.

The finished microneedle patch, designated GA@BA&Ast MNs, was cast in polydimethylsiloxane molds using vacuum centrifugal casting. Each 10 by 10 millimeter patch carries a 15 by 15 array of needles, 600 micrometers tall with 300-micrometer bases, dimensions chosen to match the anatomy of the oral epithelium so the tips cross the stratum corneum without damaging deeper tissue. Mechanical testing showed the composite needles were 1.56 times stronger than pure hyaluronic acid microneedles, comfortably exceeding the 0.15-newton threshold required for epithelial penetration. Confocal imaging of fluorescently labeled patches confirmed uniform drug distribution throughout the tips, and in rat tissue the needles delivered their cargo to depths of at least 220 micrometers, reaching the deep epithelial layers that topical formulations cannot access.

Once inserted, the transformation was dramatic. In dissolution experiments simulating the oral environment at 37 degrees Celsius and high humidity, the needle tips vanished within 2 minutes, and quantitative analysis showed that more than 85 percent of the microneedle volume had decomposed within 20 minutes, leaving minimal remnants. Spectroscopic analysis with ATR-FTIR and X-ray photoelectron spectroscopy traced the mechanism: sodium ions from the tissue fluid infiltrate the matrix and associate with the hyaluronic acid carboxylates, initiating network rearrangement, while hyperosmotic conditions further drive hydration, swelling and diffusion. Compared with chitosan-based microneedles, the release rates of astaxanthin and baicalein were enhanced by factors of 15.49 and 596.31 respectively. Crucially, the released nanofibers were then rapidly taken up by surrounding cells: within 30 minutes, the absolute amounts of astaxanthin and baicalein absorbed by oral tissue exceeded those from chitosan microneedles by 91.71-fold and 401.47-fold.

Laboratory assays revealed how the two drugs divide the therapeutic labor. In endothelial cell models, the combined nanofibers drove a scratch-wound closure rate of 87.8 percent within 24 hours, significantly outperforming astaxanthin alone at 56.4 percent, and promoted the formation of orderly tubular networks on Matrigel, indicating robust pro-angiogenic activity. The dual-drug formulation also showed the strongest scavenging of reactive oxygen species in inflamed macrophages. On the antimicrobial front, baicalein proved to be the core active component: plate assays confirmed that the released nanofibers killed and inhibited both Escherichia coli and Staphylococcus aureus, while neither hyaluronic acid nor glycyrrhizic acid alone had significant effect. In lipopolysaccharide-stimulated macrophages, the combination produced the greatest reductions in the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha among all tested groups.

The decisive test came in a rat model of oral ulceration induced by acetic acid chemical burn. Over a seven-day treatment period, ulcers treated with the full microneedle system achieved 77.3 percent wound closure, compared with just 25.5 percent natural healing in untreated animals, 34.9 percent with blank microneedles and 54.3 percent with baicalein-only patches. Macroscopically, the treated ulcers regained a healthy pink color, a sign of rapid revascularization absent in the controls. Histological examination told the same story: while untreated animals remained at the early granulation stage, the combination-treated tissue showed a smooth, continuous epithelial layer covering the wound with minimal inflammatory infiltration, hallmarks of the final maturation and remodeling phase of healing. Masson’s trichrome staining revealed uniformly organized collagen fibers resembling normal mucosa, and immunohistochemistry showed collagen deposition enhanced by 41 percent and vascular endothelial growth factor expression boosted by 47 percent relative to model controls, alongside elevated phosphorylation of PI3K and Akt, suggesting the pro-angiogenic effect runs through this well-known signaling pathway.

Safety results were equally encouraging. Major organs from treated animals showed intact architecture without inflammation, necrosis or fibrosis, the hemolysis rate stayed below the 5 percent acceptance criterion, and endothelial cell viability remained above 90 percent after exposure to patch extracts. Because the formulation relies on plant-derived compounds rather than antibiotics or corticosteroids, it sidesteps the side effects and resistance concerns associated with conventional pharmacological treatments. The researchers position the platform as a universal delivery system for hydrophobic small-molecule drugs, one whose osmolality-triggered disintegration requires no external stimulus and is tailored specifically to the wet, hyperosmotic and mechanically active environment of the mouth. If the approach translates to the clinic, the humble jellyfish sting, refined over hundreds of millions of years of evolution, may offer relief to the millions of people who suffer each year from the raw, painful lesions of oral ulcers, and potentially to patients with oral fibrosis and oral cancer as well.

Subject of Research: Osmolality-responsive dissolving microneedles for oral ulcer drug delivery

Article Title: Hyaluronic acid-based osmolality-responsive immediate-release microneedles co-loading baicalein and astaxanthin for oral ulcer therapy

Article References: Yang, J., Shi, K., Wang, J., Liu, H., Zhang, Y., Guang, X., Wang, S., Lei, W., Wang, Y., Tan, M., Ma, X., & Wu, H. (2026). Hyaluronic acid-based osmolality-responsive immediate-release microneedles co-loading baicalein and astaxanthin for oral ulcer therapy. Materials Today Bio, 41, Article 103702. https://doi.org/10.1016/j.mtbio.2026.103702

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103702

Keywords: microneedles, oral ulcers, hyaluronic acid, drug delivery, baicalein, astaxanthin, glycyrrhizic acid, nanofibers, biomimetic, osmolality-responsive, wound healing, anti-inflammatory

The research, led by Yong Wei and colleagues at Shenzhen Qianhai Shekou Free Trade Zone Hospital, together with Yuanhuan Wei of Shenzhen Nanshan People Hospital, focused on twenty clinical strains of carbapenem-resistant A. baumannii isolated at a tertiary hospital. These isolates were first characterized using multi-locus sequence typing, a genetic fingerprinting method that reads segments of several housekeeping genes to assign each strain to a sequence type. The typing revealed two dominant lineages circulating in the hospital, ST208 and ST195, both of which are recognized internationally as epidemic clones responsible for numerous hospital outbreaks of multidrug-resistant infection. Working with clinically relevant strains rather than laboratory-adapted reference bacteria gives the findings a weight that pure culture experiments often lack.

The core of the study was a systematic test of whether baicalein and ceftazidime-avibactam work better together than either drug alone. The team used checkerboard assays, a standard technique in which two antimicrobials are combined across a grid of serial dilutions to see whether their combined effect exceeds what would be expected from simple addition. The outcome is quantified by the fractional inhibitory concentration index, or FICI, a ratio in which values of 0.5 or below indicate synergism. When ceftazidime-avibactam was paired at 8/4 micrograms per milliliter with baicalein at 16 micrograms per milliliter, the combination achieved a FICI of 0.5, meeting the threshold for significant synergy against the resistant isolates.

That result is notable because ceftazidime-avibactam was never designed with A. baumannii in mind. The drug pairs ceftazidime, a third-generation cephalosporin that attacks the bacterial cell wall, with avibactam, a synthetic beta-lactamase inhibitor that shields the antibiotic from enzymatic destruction. Avibactam is effective against many of the beta-lactamases that shield Gram-negative pathogens, but A. baumannii deploys a distinct enzymatic arsenal, including OXA-type carbapenemases, that limits the drug’s utility against this organism. Baicalein appears to close part of that gap, weakening the bacterium’s defenses so that the antibiotic combination can do its work at concentrations that would otherwise fail.

Beyond killing planktonic, free-swimming bacteria, the combination also disrupted one of the most stubborn features of A. baumannii biology: its ability to form biofilms. Biofilms are organized bacterial communities encased in a self-produced matrix that adheres to catheters, ventilator tubes, and wound surfaces, and they shield resident bacteria from both antibiotics and immune attack. In the study, biofilm formation was significantly inhibited by the baicalein-antibiotic combination, with the reduction reaching statistical significance at a P value below 0.05. Because biofilm-associated infections are notoriously difficult to eradicate and often necessitate device removal, an adjuvant that suppresses biofilm development could have substantial practical value in hospital settings.

To understand how the synergy operates at the molecular level, the researchers turned to transcriptomic profiling using RNA sequencing, which measures the activity of every gene in the bacterial genome under different treatment conditions. Comparing gene expression across treatment groups, they identified 100 differentially expressed genes common to the treated populations. When these genes were mapped onto known biological pathways using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, they clustered around sulfur metabolism, butanoate metabolism, and amino acid degradation pathways. The pattern suggests that the drug combination imposes a metabolic stress that forces the bacterium to reroute core biochemical processes, potentially compromising its ability to maintain resistance machinery while under antibiotic attack.

Two molecular themes stood out in the transcriptomic data. The first involved iron metabolism genes, which were differentially regulated as the concentration of baicalein in the combination changed. Iron is an essential nutrient that bacteria must scavenge from their host environment, and disrupting iron homeostasis is an emerging strategy in antimicrobial development. The second involved members of the major facilitator superfamily, a large class of transport proteins that includes many bacterial efflux pumps. Efflux pumps are among the most important mechanisms by which bacteria expel antibiotics before the drugs can reach lethal intracellular concentrations, and their modulation by baicalein offers a plausible mechanistic explanation for why the flavonoid potentiates ceftazidime-avibactam rather than acting as a simple independent killer.

Adding a further layer of regulatory complexity, the study examined small regulatory RNAs, short non-coding RNA molecules that fine-tune gene expression in bacteria by binding messenger RNAs. The team observed a negative correlation between the expression of a small RNA called AbsR25 and an MFS transporter gene, with a correlation coefficient of negative 0.689 and a P value below 0.001. In other words, when AbsR25 levels rose, transporter expression tended to fall, consistent with the small RNA repressing the pump. The researchers validated the changes in both small RNA and messenger RNA expression using quantitative reverse transcription PCR, a technique that confirms sequencing results with independent, highly sensitive measurements. This is, to the authors’ knowledge, among the first reports linking a specific small RNA to efflux-mediated resistance modulation in A. baumannii under flavonoid-antibiotic combination therapy.

The clinical context makes the work timely. A. baumannii thrives in hospital environments, survives desiccation on surfaces for weeks, and disproportionately infects ventilated patients, burn victims, and the immunocompromised. As carbapenem resistance spreads, clinicians have been left with increasingly toxic or ineffective options, and the pharmaceutical pipeline for Gram-negative pathogens has thinned. Adjuvant strategies, in which an existing antibiotic is paired with a resistance-breaking compound, offer a faster and cheaper route to new therapies than de novo drug discovery, because the antibiotic component is already approved and its safety profile is known. Baicalein, with its established history of human use in herbal formulations and its documented antimicrobial and anti-inflammatory properties, fits the profile of a candidate adjuvant worth developing.

Important caveats remain before the combination can reach patients. The findings are entirely in vitro, derived from checkerboard assays, time-kill kinetics, and biofilm experiments in the laboratory, and the authors themselves frame the mechanisms as putative, inferred from gene expression patterns rather than directly demonstrated by functional experiments. Effective concentrations, pharmacokinetics, toxicity, and dosing in animal models and ultimately human trials have yet to be established. Nevertheless, the study establishes a concrete molecular foundation for optimizing combination regimens: by showing that baicalein modulates efflux pumps, iron homeostasis, and central metabolic pathways, it gives medicinal chemists and clinicians a rational starting point for dose selection and for screening related flavonoids. As carbapenem-resistant A. baumannii continues its global advance, the humble skullcap root may prove to hold one of the more surprising tools in the effort to push back.

Subject of Research: Synergistic activity of baicalein combined with ceftazidime-avibactam against carbapenem-resistant Acinetobacter baumannii

Article Title: Baicalein in combination with ceftazidime-avibactam exhibits synergism against carbapenem-resistant Acinetobacter baumannii in vitro

Article References: Wei, Y., Wei, Y., Xin, X., Zhang, J., He, J., Zhong, Y., Zhao, M., Li, N., & He, S. (2026). Baicalein in combination with ceftazidime-avibactam exhibits synergism against carbapenem-resistant Acinetobacter baumannii in vitro. BMC Complementary Medicine and Therapies. https://doi.org/10.1186/s12906-026-05626-6

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05626-6

Keywords: Acinetobacter baumannii, carbapenem resistance, baicalein, ceftazidime-avibactam, antibiotic synergy, biofilm inhibition, efflux pumps, iron homeostasis, transcriptomics, small regulatory RNA, antimicrobial adjuvants, hospital-acquired infection

The scientific premise rests on a growing appreciation of ferroptosis as a driver of diabetic pathology. Unlike apoptosis, ferroptosis kills cells through runaway lipid peroxidation: reactive oxygen species accumulate, iron metabolism goes awry, and the fatty membranes of cells are oxidized until they rupture. In high-glucose environments resembling diabetic tissue, the researchers showed that human umbilical vein endothelial cells, the workhorses of new blood vessel formation, suffered precisely this fate. Exposure to 33 millimolar glucose for 48 hours reduced cell viability, crippled migration in scratch and Transwell assays, and simplified the vascular networks the cells could form on Matrigel. At the molecular level, the high-glucose conditions suppressed GPX4, the glutathione-dependent enzyme that normally detoxifies lipid peroxides, while raising levels of NCOA4, a mediator of ferritinophagy that liberates iron from storage, and TFR1, the transferrin receptor that imports more iron. The result was a measurable surge in intracellular reactive oxygen species, malondialdehyde, a canonical marker of lipid peroxidation, and free ferrous iron.

Into this pathological picture the team introduced baicalein, a 5,6,7-trihydroxyflavone extracted from the roots of Scutellaria baicalensis, a plant long used in traditional East Asian medicine. The compound’s triple hydroxyl arrangement gives it exceptional antioxidant capacity, allowing it to neutralize reactive oxygen species directly and to chelate ferrous iron into stable complexes that cannot participate in Fenton reactions, the chemistry that converts hydrogen peroxide into the most destructive hydroxyl radicals. In the new experiments, baicalein at 20 micromolar, a concentration shown to be non-toxic up to 100 micromolar, largely restored endothelial viability, migration and tube formation under both high-glucose stress and treatment with RSL-3, a chemical that induces ferroptosis by covalently inactivating GPX4. The drug upregulated GPX4, dampened NCOA4 and TFR1, and pushed down cellular levels of reactive oxygen species, malondialdehyde and free iron, confirming that its protective effect operates specifically through the ferroptosis machinery rather than through some generic stress response.

The mechanistic core of the study lies in the Keap1/NRF2/HIF-1α signaling axis. Under resting conditions, the protein Keap1 binds NRF2, the master transcriptional regulator of antioxidant defense, and tags it for degradation. Oxidative stress normally pries this pair apart, freeing NRF2 to enter the nucleus and activate antioxidant response elements in genes such as GPX4. The researchers found that high glucose or RSL-3 pushed the system the wrong way, elevating Keap1 while suppressing NRF2 and, downstream, HIF-1α, the oxygen-sensing transcription factor that drives vascular endothelial growth factor production and angiogenesis. Molecular docking predicted that baicalein binds the Kelch domain of Keap1 with a favorable energy of minus 8.73 kilocalories per mole, forming hydrogen bonds with residues including VAL-420, VAL-512 and VAL-467. Co-immunoprecipitation then confirmed that baicalein promotes dissociation of the Keap1–NRF2 complex in cells. When the team knocked down NRF2 with lentiviral shRNA, or blocked it pharmacologically with ML385, baicalein’s anti-ferroptotic protection collapsed, GPX4 fell, iron import genes rose, and oxidative markers climbed, demonstrating that NRF2 is essential to the drug’s action and that NRF2 in turn sustains HIF-1α expression through a validated antioxidant response element in the HIF1A enhancer.

Translating this chemistry into a clinically usable dressing required solving a stubborn formulation problem: baicalein is poorly soluble in water, so free drug applied to a wound would never reach therapeutic concentrations. The team’s solution borrows from plant defense chemistry itself. Glycyrrhizic acid, a natural triterpenoid from licorice, self-assembles in aqueous solution into nanofibers that encapsulate baicalein, dramatically enhancing its solubility and enabling sustained release. These nanofibers were then complexed with gelatin and zinc ions at 40 degrees Celsius and gelled overnight, producing a dual physically cross-linked network held together by metal-coordination bonds between zinc and the carboxyl groups of glycyrrhizic acid and by hydrogen bonds between gelatin and the nanofibers. Infrared spectroscopy tracked the structural evolution, showing a broadened, shifted O–H peak at 3267 inverse centimeters indicative of the hydrogen-bonded network and the disappearance of characteristic baicalein-glycyrrhizic acid peaks upon zinc coordination.

Mechanical testing revealed a material well matched to living tissue. Rheology confirmed solid-dominated viscoelasticity, with the storage modulus exceeding the loss modulus across the tested frequency range, and the formulation containing 0.4 percent baicalein-glycyrrhizic acid nanofibers showed the highest storage modulus and greatest critical strain. Uniaxial compression yielded a Young’s modulus of about 33 kilopascals with fracture at 42 percent strain, soft enough to deform with skin, while lap-shear testing on porcine skin recorded an adhesive strength of roughly 62 kilopascals, enough to keep the patch anchored through joint flexion. The hydrogel also proved environmentally responsive. At physiological pH 7.4 it swelled to 186 percent of its dry weight, but at the acidic pH 5.5 characteristic of diabetic wounds, protonation of carboxyl groups compacted the network and limited swelling to 106 percent. Drug release was correspondingly slower in acid, extending baicalein retention exactly where diabetic wounds need it most, although matrix metalloproteinase-9 in simulated wound fluid accelerated degradation, a property that could allow the dressing to yield its payload as it dissolves in the enzyme-rich wound bed.

Safety and antimicrobial performance rounded out the preclinical profile. Live-dead staining and proliferation assays showed the composite hydrogel actually promoted endothelial cell growth, hemolysis rates stayed below the 5 percent safety threshold, and histological examination of heart, liver, spleen, lung and kidney tissue from treated rats revealed no pathological changes. Released baicalein is metabolized locally and systemically by glucuronidation and sulfation and cleared renally, limiting systemic exposure. Against Staphylococcus aureus and Escherichia coli, the two flagship wound pathogens, the components showed only modest activity individually, but the full composite achieved a bactericidal rate exceeding 70 percent against S. aureus, a synergy attributed to baicalein and glycyrrhizic acid disrupting bacterial walls while zinc ions inhibit metabolic enzymes. When cells were challenged with RSL-3, the hydrogel reduced reactive oxygen species, malondialdehyde and ferrous iron more effectively than any other formulation, approaching the performance of Ferrostatin-1, a benchmark ferroptosis inhibitor, and it also blunted hydrogen peroxide-induced apoptosis by activating the PI3K/Akt survival pathway.

The decisive test came in diabetic rats. The team induced diabetes with streptozotocin, excised one-centimeter full-thickness wounds on the animals’ backs, and treated them with phosphate buffer, free baicalein, baicalein-glycyrrhizic acid nanofibers, the gelatin-zinc scaffold without drug, or the complete composite. By day nine the full hydrogel had closed 96.4 percent of wound area, compared with 89.1 percent for the drug-free scaffold, 84.6 percent for the nanofibers alone and 76.5 percent for free baicalein. Hematoxylin and eosin staining showed reduced wound width and complete epithelialization in the composite group, while Masson’s trichrome revealed abundant, well-organized collagen deposition. Immunofluorescence for CD31 and alpha-smooth muscle actin documented a surge in mature new blood vessels, and immunohistochemistry confirmed the molecular signature seen in the dish: GPX4 up, NCOA4 and TFR1 down, Keap1 suppressed, and both NRF2 and HIF-1α elevated. Tumor necrosis factor-alpha levels fell as well, pointing to a calming of the chronic inflammation that normally stalls diabetic repair.

The work, led by Haiting Zou, Qian Tan and colleagues at Nanjing institutions, positions the baicalein-loaded glycyrrhizic acid hydrogel as a multifunctional platform that simultaneously fights infection, quenches oxidative stress, blocks ferroptotic endothelial death and stimulates revascularization, all from a single bio-derived dressing. Compared with earlier baicalein delivery systems built on Schiff-base chemistry, zeolitic imidazolate frameworks or chitosan, the dual-crosslinked supramolecular network offers superior mechanical strength and pH-tuned drug retention. The researchers caution that the findings rest on rodent models and that the Keap1/NRF2/HIF-1α mechanism, while strongly supported by knockdown, inhibitor and docking data, operates within a web of additional pathways including PI3K/Akt-mediated survival signaling. Even so, the strategy of targeting ferroptosis through a self-assembling, plant-inspired biomaterial offers a compelling template for the next generation of intelligent wound dressings, and it underscores how molecules refined by plant evolution over millions of years can be re-engineered, with the help of licorice nanofibers and a dash of zinc, into therapies for one of modern diabetes care’s most intractable problems.

Subject of Research: A supramolecular hydrogel delivering baicalein to inhibit ferroptosis and accelerate diabetic wound healing

Article Title: Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing

Article References: Zou, H., Chen, J., Huang, Y., Li, J., Yuan, X., Chen, T., Ding, Y., Yang, P., Zheng, D., Chen, G., & Tan, Q. (2026). Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing. Journal of Advanced Research, 88, 841-853. https://doi.org/10.1016/j.jare.2026.01.024

Image Credits: AI Generated

DOI: Not provided

Keywords: diabetic wounds, ferroptosis, baicalein, glycyrrhizic acid, hydrogel, NRF2, HIF-1α, GPX4, angiogenesis, zinc ions, wound dressing, nanofibers