<p>Oral mucositis (OM) is characterized by local pain and breakdown of the mucosa barrier, resulting in severe infection. While the topical application of hydrogel-based delivery systems can prolong the therapeutic duration of clinically administered small-molecule drugs, their therapeutic outcomes are compromised by the lack of transmucosal permeation and inflammatory microenvironment-triggered drug release. Herein, we report a supramolecular strategy for designing guanosine-fibril hydrogels and derived microneedle patches, in which tavaborole (Ta), crisaborole (Cr), and strontium (Sr²⁺) ions serve dual roles as structural building blocks and biofunctional agents. Compared to conventional G₄·K⁺ fibrils assembled via hydrogen bonding, base stacking, and ion dipole interactions, the unique G₄·Sr²⁺-Ta/Cr fibrils further incorporate Ta/Cr and Sr²⁺ through the formation boronic ester bond on guanosine and through the development of G-quartets as cation receptors, respectively. In this design, Ta/Cr and Sr²⁺ mechanically reinforce the hydrogel assembly through additional hydrophobic interactions and ion-pair recognition, while synergistically combining multiple biofunctionalities, including antimicrobial/anti-inflammatory effects (Ta/Cr), pro-angiogenic activity (Sr²⁺), and reactive oxygen species (ROS) scavenging (guanosine). Moreover, the optimized gelation process enables the fabrication of G₄·Sr²⁺-Ta/Cr microneedle patches, exhibiting pseudomembrane-penetrating capability and ROS-triggered drug release via boronic ester hydrolysis for potential therapeutic OM applications. <i>In vivo</i> experiments on mice confirm the treatment efficacy in controlling OM-associated inflammation, modulating oral microbiota homeostasis, promoting angiogenesis at ulcer sites, thereby enabling effective therapy. This work realizes multifunctional integration via hierarchical structural designs, extending guanosine supramolecular assemblies into bioactive platforms with biomedical functions for OM treatment.</p>