Boron-doped mesoporous bioactive glass nanoparticles as a dual-delivery platform for tetracycline and phytochemicals: A synergistic strategy against multidrug-resistant bacteria

Abstract

Antimicrobial resistance (AMR) and biofilm-associated tolerance substantially limit the effectiveness of conventional antibiotic therapy. This study investigated boron-doped mesoporous bioactive glass (B-MBG) nanoparticles as a dual-payload delivery system for the combined administration of tetracycline and selected hydrophobic phytochemical adjuvants, including berberine, curcumin, and resveratrol. The platform was designed to improve antibacterial and antibiofilm activity while facilitating the delivery of poorly soluble natural compounds. B-MBG nanoparticles were synthesized using a sol-gel method. Tetracycline and each phytochemical were nominal 2:1 input mass ratio. Particle morphology and structure were characterized by SEM, SEM-EDS, DLS, N₂ adsorption–desorption analysis, and XRD. Biological activity was examined by planktonic microdilution at 24 and 48 h, disk diffusion, and a 72-h crystal violet biofilm assay. Cytocompatibility was evaluated in HaCaT keratinocytes at 24, 48, and 72 h. The resulting datasets were analyzed using multiparametric statistical methods and principal component analysis. B-MBG nanoparticles exhibited a predominantly uniform spherical morphology with particle sizes of approximately 100-150 nm. The mesoporous structure had a specific surface area of 156.14 m² g⁻¹ and a mean pore size of 4.27 nm. XRD analysis confirmed an amorphous borosilicate network accompanied by microcrystalline calcite. Co-loading with berberine or resveratrol markedly improved the antibacterial activity of carrier-bound tetracycline, decreasing the planktonic IC₅₀ against E. coli by 13- to 33-fold relative to Tet-B-MBG and producing IC₅₀ estimates below the detection threshold (<0.5 µg mL⁻¹) against MRSA. Free phytochemicals frequently stimulated biofilm formation at sub-inhibitory concentrations, particularly in E. coli and S. epidermidis. Incorporation into the B-MBG co-delivery system reduced this stimulation; with Tet-Res-B-MBG the mean biofilm response was 152.6 and 101.9 percentage points higher than with free resveratrol (q<0.05), although biofilm biomass remained above the untreated control. Cytocompatibility was time dependent, with the reduction in cell viability observed at 24 h followed by cell viabilities of 78–115% at 48–72 h within the tested therapeutic concentration range. B-MBG-mediated co-delivery enhanced the antibacterial activity of tetracycline and reduced the pro-biofilm effects of free phytochemical adjuvants. Rather than acting as an intrinsically antimicrobial carrier, B-MBG provided a tunable matrix through which payload selection and controlled exposure could be used to improve biological performance. These findings support B-MBG nanoparticles as a customizable anti-infective delivery platform for combining conventional antibiotics with poorly soluble natural adjuvants, although further validation in more complex biological and translational models is required.

Keywords

• Antimicrobial resistance
• biofilm inhibition
• dual-drug delivery
• mesoporous bioactive glass
• phytochemical adjuvants

Thanks

Experimental studies were conducted at the Science and Advanced Technology Application and Research Center of Istanbul Medeniyet University. This research was funded by the Health Institutes of Türkiye (Türkiye Saglik Enstituleri Baskanligi - TUSEB), grant number 11985.

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