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

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 <i>Escherichia coli</i> remained resistant, Gram-positive <i>Staphylococcus epidermidis</i> 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.