Exploring Gluconamide-Modified Silica Nanoparticles of Different Sizes as Effective Carriers for Antimicrobial Photodynamic Therapy

Antimicrobial resistance (AMR), a consequence of the ability of microorganisms, especially bacteria, to develop resistance against conventional antibiotics, hampering the treatment of common infections, is recognized as one of the most imperative health threats of this century. Antibacterial photodynamic therapy (aPDT) has emerged as a promising alternative strategy, utilizing photosensitizers activated by light to generate reactive oxygen species (ROS) that kill pathogens without inducing resistance. In this work, we synthesized silica nanoparticles (NPs) of different sizes (20 nm, 80 nm, and 250 nm) functionalized with the photosensitizer Rose Bengal (RB) and a gluconamide ligand, which targets Gram-negative bacteria, to assess their potential in aPDT. Comprehensive characterization, including dynamic light scattering (DLS) and photophysical analysis, confirmed the stability and effective singlet oxygen production of the functionalized nanoparticles. Although the surface loading density of Rose Bengal was constant at the nanoparticle external surface, RB loading (in mg/g nanoparticle) was size-dependent, decreasing with increasing nanoparticle diameter. Further, the spherical geometry of nanoparticles favored smaller nanoparticles for antibacterial PDT, as this maximizes the surface contact area with the bacteria wall, with the smallest (20 nm) and intermediate (80 nm) particles being more promising. Bacterial assays in <i>E. coli</i> revealed minimal dark toxicity and significant light-activated phototoxicity for the RB-loaded nanoparticles. The addition of gluconamide notably enhanced phototoxic activity, particularly in the smallest nanoparticles (RB-G-20@SiNP), which demonstrated the highest phototoxicity-to-cytotoxicity ratio. These findings indicate that small, gluconamide-functionalized silica nanoparticles are highly effective for targeted aPDT, offering a robust strategy to combat AMR.