The increasing prevalence of multidrug-resistant bacteria necessitates alternative therapeutic strategies that combine antimicrobial efficacy with immunomodulatory properties. Here, we report the immunostimulatory activity and antibacterial potential of the amino-functionalized metal-organic framework MIL-101(Al)-NH2 as a carrier for penicillin (PEN) and hypericin (Hyp), a photodynamically active compound. Structural and physicochemical characterization confirmed successful encapsulation of PEN, Hyp, and their combination within MIL-101(Al)-NH2, with distinct effects on porosity, release kinetics, and thermal stability. Drug release studies revealed rapid Hyp liberation triggered by serum components, whereas PEN exhibited a biphasic, diffusion-controlled profile. Using a quail chorioallantoic membrane (CAM) model, we demonstrated that MIL-101(Al)-NH2 enhances interferon-α expression, indicating intrinsic immunostimulatory activity, and that Hyp-loaded systems promote angiogenic responses. In a bacterial infection CAM model, MIL-101(Al)-NH2 carriers loaded with Hyp or Hyp/PEN induced immunomodulatory changes and, upon photodynamic activation, inhibited bacterial growth. While Gram-negative Escherichia coli remained resistant, Gram-positive Staphylococcus epidermidis was effectively suppressed by photodynamic therapy (PDT), and Hyp/PEN co-delivery overcame bacterial resistance to PEN. These results highlight MIL-101(Al)-NH2 as a multifunctional nanoplatform with immunostimulatory capacity and PDT-enhanced antibacterial activity, offering a promising strategy to combat antibiotic resistance and infections associated with medical implants.

Center for Interdisciplinary Biosciences Technology and Innovation Park Pavol Jozef Šafárik University in Košice Jesenná 5 SK 041 54 Košice Slovakia

Department of Biochemistry Faculty of Science Pavol Jozef Šafárik University in Košice Moyzesova 11 SK 041 54 Košice Slovakia

Department of Biophysics Faculty of Science Pavol Jozef Šafárik University in Košice Jesenná 5 SK 041 54 Košice Slovakia

Department of Chemistry Faculty of Science University of Ostrava 30 Dubna 22 CZ 701 03 Ostrava Czech Republic

Department of Inorganic Chemistry Faculty of Science Pavol Jozef Šafárik University in Košice Moyzesova 11 SK 041 54 Košice Slovakia

Institute of Animal Biochemistry and Genetics Centre of Biosciences Slovak Academy of Sciences Dúbravská Cesta 9 SK 840 05 Bratislava Slovakia

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