DISCUSSION

The hydrogel-based WIRES developed in this study introduced a biointegrated platform that connected biological functions and digital information at the immune interface. By integrating radio-frequency circuits with enzymatically responsive hydrogels, WIRES enabled monitoring of inflammation activity and localized immunomodulation for periodontal disease. Unlike conventional rigid sensors or passive drug carriers, this platform coupled disease-specific biochemical recognition with wireless feedback and therapeutic intervention, providing a closed-loop strategy for precision care. With its tissue-mimicking, biocompatible and adhesive properties, the hydrogel layer served as a soft biointerface that allowed the flexible patch to conform to the moist gingival surface, providing an accessible option for patients with mild-to-moderate periodontal disease. For individuals with severe periodontitis, the miniaturized, flexible device could be painlessly implanted into the periodontal pocket following conventional subgingival scaling, allowing for seamless integration into routine dental care. WIRES was designed for temporary use and can be removed or replaced after treatment. For future development, transient and biodegradable materials could be incorporated to enable fully degradable bioelectronic devices [54,55].

A key advantage of WIRES lies in its ability to transduce inflammation-associated biochemical activity into measurable wireless signals, facilitating non-invasive detection of the local immune microenvironment. Here, MMP-9 was employed as a representative biomarker of periodontal inflammation. While conventional clinical assessments, including visual inspection and radiography, were limited by delayed detection and limited sensitivity to early-stage inflammation, the WIRES provided dynamic tracking of the disease activity. Compared with previously reported MMP-9 sensing methods (Table S4), the hydrogel-based sensor in this study was designed for in situ wireless monitoring rather than conventional laboratory-based biomarker detection. The peptide-functionalized hydrogel directly responded to MMP-9 enzymatic activity through peptide cleavage, which was closely associated with active inflammatory processes. In addition, the wireless readout supported in situ monitoring at the oral tissue interface, which was difficult to achieve with solution-based or benchtop detection methods. This modular sensing strategy could also be extended to detect other proteases or molecular targets by substituting recognition motifs (such as other peptide or aptamer sequences) within the hydrogel [33,56,57], making it a scalable platform for inflammatory disease diagnostics.

Beyond sensing, WIRES also offered inflammation-triggered delivery of immune-regulatory miRNAs, linking molecular diagnostics with on-demand, localized therapy. Compared with reported local drug delivery systems for periodontal therapy (Table S5), WIRES was distinguished by the integration of miRNA immunomodulation, MMP-responsive local release and wireless sensing of inflammatory activity. We identified let-7c as a crucial downregulated miRNA in periodontitis and loaded it into the hydrogel for bioresponsive release, enabling multifaceted, gene-level modulation of the local inflammatory microenvironment. The MMP-responsive hydrogel coupled drug release to disease-related enzymatic activity, rather than relying only on passive release. Importantly, hydrogel degradation not only delivered the drug but also generated a wireless signal, allowing feedback to guide timely drug replenishment or prompt further clinical intervention if necessary.

Besides, the hydrogel matrix was compatible with a variety of bioactive agents, such as nucleic acids, nanoparticles or even engineered bacteria [24,41,58], supporting future expansion toward regenerative and comprehensive interventions. From a translational perspective, localized miRNA delivery with hydrogel may reduce systemic exposure and potential off-target effects compared with systemic administration [59,60]. The non-viral, peptide-functionalized gelatin matrix also provided a biocompatible and biodegradable carrier for local periodontal delivery. While the current animal study validated the immunomodulatory effect of let-7c released from the hydrogel, future studies are needed to evaluate the patch for local therapeutic delivery in large-animal periodontal models.

In summary, we developed a bioresponsive hydrogel-based bioelectronic platform capable of wireless biosensing and on-demand immunomodulation. By integrating functionalized biomaterials with soft electronics, the system established a dynamic interface between the immune microenvironment and digital feedback networks, offering opportunities for adaptive management of chronic inflammation. This bioelectronic system held potential for broader applications to other inflammation-related diseases, such as wound healing, osteoarthritis or autoimmune disorders, providing a platform to explore dynamic interactions between electronic interfaces, bioactive hydrogels and the living biosystems.