Key Takeaways & Executive Findings
- •• • The G4·Sr2+-Ta/Cr fibrils incorporate tavaborole and crisaborole via boronic ester bonds and Sr2+ via G-quartet cation recognition, achieving dual structural reinforcement and bioactivity, unlike conventional G4·K+ fibrils. • • The optimized gelation process enables fabrication of microneedle patches with pseudomembrane-penetrating capability, addressing the bottleneck of transmucosal permeation in topical OM therapies. • • ROS-triggered drug release is achieved via boronic ester hydrolysis, ensuring on-demand therapeutic delivery specifically in the inflammatory microenvironment. • • In vivo mouse experiments confirm treatment efficacy in controlling OM-associated inflammation, modulating oral microbiota homeostasis, and promoting angiogenesis at ulcer sites, validating the multifunctional platform.
Abstract
Oral mucositis (OM) is a debilitating complication of cancer therapy, characterized by severe pain, mucosal barrier breakdown, and infection risk. Current hydrogel-based topical systems suffer from poor transmucosal permeation and lack of inflammatory microenvironment-triggered drug release. Here, we report a supramolecular strategy for designing guanosine-fibril hydrogels and derived microneedle patches. Tavaborole (Ta), crisaborole (Cr), and strontium (Sr2+) ions serve dual roles as structural building blocks and biofunctional agents. Unlike conventional G4·K+ fibrils, the unique G4·Sr2+-Ta/Cr fibrils incorporate Ta/Cr via boronic ester bonds on guanosine and Sr2+ through G-quartet cation recognition. This design mechanically reinforces the hydrogel through additional hydrophobic interactions and ion-pair recognition, while synergistically providing antimicrobial/anti-inflammatory effects (Ta/Cr), pro-angiogenic activity (Sr2+), and reactive oxygen species (ROS) scavenging (guanosine). The optimized gelation process enables fabrication of microneedle patches with pseudomembrane-penetrating capability and ROS-triggered drug release via boronic ester hydrolysis. In vivo mouse experiments confirm efficacy in controlling OM-associated inflammation, modulating oral microbiota homeostasis, and promoting angiogenesis at ulcer sites. This work demonstrates multifunctional integration via hierarchical structural design, extending guanosine supramolecular assemblies into bioactive platforms for OM treatment.
1. Introduction
Oral mucositis (OM) remains a formidable clinical challenge in oncology, arising as a frequent complication of chemotherapy and radiotherapy. The underlying pathophysiology involves elevated reactive oxygen species (ROS) and excessive pro-inflammatory cytokines, leading to mucosal barrier disruption, ulceration, and severe pain. Conventional topical treatments, such as oral rinses and anti-inflammatory agents, suffer from poor transmucosal permeability and lack of controlled release, resulting in suboptimal therapeutic outcomes and significant patient distress. The dysregulation of oral microbiota further perpetuates inflammation, complicating effective management.
This study introduces a supramolecular strategy that directly tackles these bottlenecks. By engineering guanosine-based fibrils with tavaborole, crisaborole, and strontium ions, the authors create a hydrogel that not only provides structural integrity but also integrates multiple biofunctions: antimicrobial, anti-inflammatory, pro-angiogenic, and ROS-scavenging. The derived microneedle patches overcome the permeation barrier, while ROS-triggered drug release ensures localized, on-demand therapy. This hierarchical design offers a promising platform for effective OM treatment, addressing both the clinical and biological complexities of the disease.
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Jianhua Li, Jialu Chen, Beibei Zhang, Pingyi Zhu, Xingsen Yang, Junhao Liang, Yuan He, Yong Hu, Jianzhong Du (2026). Inflammatory microenvironment-triggered oral mucositis treatment by guanosine microneedles. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3782-0
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Frequently Asked Questions
What are the specific mechanical properties of the G4·Sr2+-Ta/Cr microneedle patches that enable pseudomembrane penetration?
The optimized gelation process yields microneedle patches with sufficient mechanical strength to penetrate the pseudomembrane, as demonstrated in vivo. The incorporation of Ta/Cr and Sr2+ enhances the structural integrity through hydrophobic interactions and ion-pair recognition, providing the necessary stiffness for insertion.
How does the ROS-triggered drug release kinetics compare to conventional diffusion-based systems?
The boronic ester hydrolysis is specifically triggered by ROS, enabling on-demand release in the inflammatory microenvironment. This contrasts with passive diffusion, which often leads to premature drug leakage and suboptimal therapeutic windows. The ROS-responsive mechanism ensures localized and timely drug delivery, as evidenced by in vivo efficacy.
What is the long-term stability of the microneedle patches under physiological conditions?
The supramolecular fibrils are stabilized by multiple non-covalent interactions, including hydrogen bonding, base stacking, and ion coordination. While specific degradation rates are not detailed, the in vivo efficacy over the treatment period suggests adequate stability. Further studies would be needed to quantify shelf-life and in vivo degradation profiles.
How does the incorporation of Sr2+ affect the biocompatibility and potential toxicity of the microneedle patches?
Sr2+ is known for its pro-angiogenic and bone-regenerative properties, and its use in biomedical applications is well-established. The study demonstrates in vivo efficacy without reported adverse effects, suggesting acceptable biocompatibility. However, comprehensive toxicity assessments, including long-term systemic exposure, would be necessary for clinical translation.
What are the scalability challenges for manufacturing these microneedle patches at clinical grade?
The fabrication involves a supramolecular self-assembly process that is inherently scalable, but challenges include maintaining batch-to-batch consistency in fibril formation and microneedle geometry. The use of clinically relevant molecules (Ta, Cr, Sr2+) and the simplicity of the gelation process are advantageous. Further optimization of manufacturing parameters and quality control would be required for large-scale production.
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