Transcriptomics-informed design of a dual phytochemical hydrogel enables immuno-redox modulation and accelerated...

Infected burn wounds require advanced integrative therapies capable of addressing both microbial burden and dysregulated inflammation. This study reports a transcriptomics-guided phytochemical-engineered alginate hydrogel designed to modulate immuno-redox pathways and promote regenerative repair, offering a multi-targeted strategy for infected burn management. Transcriptomic profiling, network pharmacology, and molecular docking were employed to identify inflammatory mediators and transcriptional regulators associated with infected burn pathology, including IL1B, TNF, FOS, and CXCL8. A Conessine- and α-Mangostin-loaded alginate hydrogel (CαMLAH) was synthesized, optimized using a Quality-by-Design approach, and characterized for physicochemical properties. In-vitro assessments included drug release and biocompatibility evaluations, while therapeutic efficacy was investigated in a murine infected burn model using wound closure kinetics, bacterial burden, biochemical assays, histopathology, and molecular analyses. Transcriptomic analysis identified differential regulation of inflammatory genes and transcription factors associated with immune signaling pathways. Molecular docking predicted favorable interactions between the phytoconstituents and inflammatory mediators. The optimized CαMLAH formulation exhibited physicochemical stability, sustained drug release, favorable rheological characteristics, excellent hemocompatibility, and antibacterial activity. In-vivo treatment was associated with accelerated wound closure, reduced bacterial burden, and improved inflammatory and redox profiles. Histological and molecular findings further suggested enhanced re-epithelialization, collagen organization, and attenuation of NF-κB/AP-1-associated transcriptional programs, accompanied by reduced expression of REL, JUNB, and related transcription factors. Collectively, these findings support the potential utility of CαMLAH as a transcriptomics-guided, multifunctional therapeutic platform for infected burn wounds. The integration of molecular target prioritization with biomaterial engineering highlights the potential of transcriptomics-guided phytochemical formulations for advanced wound management and infection-associated inflammatory disorders.