The Immunostimulatory Effect of MIL-101(Al)-NH2 In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy

Máčajová, Mariana; Ambro, Ľuboš; Meta, Majlinda; Zauška, Ľuboš; Gulyásová, Terézia; Bilčík, Boris; Čavarga, Ivan; Zelenková, Gabriela; Sedlák, Erik; Almáši, Miroslav; Huntošová, Veronika

doi:10.3390/ijms262311681

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The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy

by

Mariana Máčajová

^1,†

,

Ľuboš Ambro

^2,†

,

Majlinda Meta

¹,

Ľuboš Zauška

³,

Terézia Gulyásová

^2,4,

Boris Bilčík

¹

,

Ivan Čavarga

¹,

Gabriela Zelenková

⁵

,

Erik Sedlák

^2,6

,

Miroslav Almáši

^3,*

and

Veronika Huntošová

^1,2,*

¹

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

²

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

³

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

⁴

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

⁵

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

⁶

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

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(23), 11681; https://doi.org/10.3390/ijms262311681

Submission received: 5 October 2025 / Revised: 23 November 2025 / Accepted: 1 December 2025 / Published: 2 December 2025

(This article belongs to the Special Issue New Molecular Insights into Antimicrobial Photo-Treatments)

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Abstract

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.

Keywords: metal-organic frameworks; MIL-101(Al)-NH₂; immune response; antibacterial photodynamic therapy; bacterial resistance; penicillin; hypericin; chorioallantoic membrane model

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MDPI and ACS Style

Máčajová, M.; Ambro, Ľ.; Meta, M.; Zauška, Ľ.; Gulyásová, T.; Bilčík, B.; Čavarga, I.; Zelenková, G.; Sedlák, E.; Almáši, M.; et al. The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy. Int. J. Mol. Sci. 2025, 26, 11681. https://doi.org/10.3390/ijms262311681

AMA Style

Máčajová M, Ambro Ľ, Meta M, Zauška Ľ, Gulyásová T, Bilčík B, Čavarga I, Zelenková G, Sedlák E, Almáši M, et al. The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy. International Journal of Molecular Sciences. 2025; 26(23):11681. https://doi.org/10.3390/ijms262311681

Chicago/Turabian Style

Máčajová, Mariana, Ľuboš Ambro, Majlinda Meta, Ľuboš Zauška, Terézia Gulyásová, Boris Bilčík, Ivan Čavarga, Gabriela Zelenková, Erik Sedlák, Miroslav Almáši, and et al. 2025. "The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy" International Journal of Molecular Sciences 26, no. 23: 11681. https://doi.org/10.3390/ijms262311681

APA Style

Máčajová, M., Ambro, Ľ., Meta, M., Zauška, Ľ., Gulyásová, T., Bilčík, B., Čavarga, I., Zelenková, G., Sedlák, E., Almáši, M., & Huntošová, V. (2025). The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy. International Journal of Molecular Sciences, 26(23), 11681. https://doi.org/10.3390/ijms262311681

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The Immunostimulatory Effect of MIL-101(Al)-NH₂ In Vivo and Its Potential to Overcome Bacterial Resistance to Penicillin Enhanced by Hypericin-Induced Photodynamic Therapy

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