Francesco Trotta

Xenon (Xe) is an inert noble gas receiving increasing attention in medical research due to its anesthetic properties, ability to regulate metabolic processes, and broad organoprotective effects. Due to its small size and non-covalent intermolecular interactions, Xe can be encapsulated within α-cyclodextrin (α-CD). In this study, we combine a theoretical study based on molecular mechanics (MM) and molecular dynamics (MD) simulations with the synthesis and characterization of the α-CD/Xe inclusion complex. During the MD simulations, surface interactions and the formation of inclusion complexes, with Xe atoms encapsulated within the α-CD cavity, were observed in aqueous solution. As the Xe concentration in water increased, α-CD/Xe inclusion complexes with 1:1, 1:2, and 1:3 stoichiometries were formed and remained stable over time, suggesting increasingly effective encapsulation at higher pressures. Following this computational investigation, experimental work was conducted to synthesize and characterize the α-CD/Xe inclusion complex using a liquid-phase encapsulation method. The complexes were prepared at Xe loading pressures of 2, 4, 6, and 8 bar. Thermogravimetric analysis (TGA) revealed weight loss between 100 and 200 °C. The effective encapsulation of Xe was also confirmed by solid-phase microextraction coupled with gas chromatography–mass spectrometry (SPME-GC-MS), which detected the characteristic m/z signals of Xe and allowed monitoring of its release over time upon contact with aqueous solution.

A non-motile bacterium, Mycobacterium tuberculosis (Mtb), causes tuberculosis (TB), an infection of the lower respiratory tract. Currently, rifampicin, isoniazid, ethambutol, and pyrazinamide are used as first-line treatment for drug-susceptible TB for two months, followed by four months of rifampicin and isoniazid. This treatment plan is linked to serious hepatic, dermatological, and hematopoietic adverse effects. The exploration of natural substances like quercetin for treating TB was driven by the significant side effects of the standard therapy protocol. Protein-coated gold nanopopcorns were developed as a dry-powder inhaler to deliver tailored medication to the lungs. The objective of this research article was to assess the effectiveness of quercetin-loaded gold nanopopcorns against Mtb H37Ra cells. The gold nanopopcorns prepared using the Turkevich method and subsequently coated with maleylated BSA (m-BSA) showed an adsorption efficiency of 87.02 ± 2.82%, particle size of 153.2 ± 26.45 nm, and a zeta potential of 29.3 ± 7.80 mV. In vitro release studies showed rapid initial release within 2 h, with a total drug release of 79.85 ± 1.33% over 24 h, with inhibition of 56.36% of H37Ra cells (IC₅₀ = 2 μg/mL). These findings provide preliminary evidence for the potential of PNPs as a pulmonary quercetin delivery platform, warranting further evaluation in macrophage-based and tuberculosis disease models.

Tyrosol and kynurenic acid (KYNA) are natural antioxidants with complementary radical-scavenging and photo-absorbing properties, but their combined performance in a cosmetic formulation has not been reported. We developed an oil-in-water (O/W) emulsion containing tyrosol, KYNA, or a 1:1 mixture, using an unloaded emulsion as control. Formulations were evaluated for four weeks at 4, 25, and 40 °C using differential scanning calorimetry (DSC), rheology, spreadability, centrifugation, pH, DPPH antioxidant activity, HPLC quantification and release through a dialysis membrane; compositional stability was assessed by elemental (CHN) analysis. Chemical equilibrium parameters showed a consistent trend: the first week represented a maturation phase, likely reflecting redistribution of actives within the matrix, followed by a stable equilibrium state. The results are therefore discussed as initial versus equilibrated conditions. At equilibrium, the binary formulation maintained a skin-compatible pH (4.40 ± 0.04) with lower variability than single-active systems. HPLC confirmed nominal loading without degradation (0.89 ± 0.08% tyrosol, 0.97 ± 0.10% KYNA, and 1.00 ± 0.18% total in the mixture). DPPH analysis of standards revealed cooperative antioxidant enhancement in the mixture, exceeding the activity of either compound alone. In the creams, this produced a modest but reproducible antioxidant effect (9.00 ± 3.94%, 8.91 ± 3.56%, and 7.02 ± 3.59% inhibition for tyrosol, KYNA, and the mixture, respectively, versus 0.67 ± 4.80% for the control). The mixture showed a significant sub-additive interaction only at 4 °C (p = 0.014). Mechanical stability depended mainly on storage temperature: centrifugation-induced phase separation increased from 8% to 28% between weeks 2 and 4 and was largely prevented at room temperature or above. In the dialysis model, the mixture markedly increased tyrosol release while reducing KYNA release, a behavior tentatively attributed to proton-exchange/keto–enol interactions. Overall, room temperature was the optimal storage condition, and the tyrosol-KYNA combination emerged as a stable, skin-compatible antioxidant system for topical application.

Xenon (Xe) is an inert noble gas receiving increasing attention in medical research due to its anesthetic properties, ability to regulate metabolic processes, and broad organoprotective effects. Due to its low molecular weight and small size, Xe can be encapsulated within α-cyclodextrin (α-CD). In this study, we combine a theoretical study based on molecular mechanics (MM) and molecular dynamics (MD) simulations with the synthesis and characterization of the α-CD/Xe inclusion complex. During the MD simulations, surface interactions and the formation of inclusion complexes, with Xe atoms encapsulated within the α-CD cavity, were observed in aqueous solution. As the Xe concentration in water increased, α-CD/Xe inclusion complexes with 1:1, 1:2, and 1:3 stoichiometries were formed and remained stable over time, suggesting increasingly effective encapsulation at higher pressures. Following this computational investigation, experimental work was conducted to synthesize and characterize the α-CD/Xe inclusion complex using a liquid-phase encapsulation method. The complexes were prepared at pressures of 2 and 4 bar. Thermogravimetric analysis (TGA) revealed weight loss. The effective encapsulation of Xe was also confirmed by solid-phase microextraction coupled with gas chromatography - mass spectrometry (SPME-GC-MS), which detected the characteristic m/z signals of Xe and allowed monitoring of its release over time upon contact with aqueous solution.

Dextrin-based nanosponges (D-NS) are promising candidates for oral drug delivery due to their biocompatibility, mucoadhesive properties, and tunable swelling behavior. In this study, pH-sensitive nanosponges were synthesized using β-cyclodextrin (β-CD), GluciDex^®2 (GLU2), and KLEPTOSE^® Linecaps (LC) as building blocks, crosslinked with pyromellitic dianhydride (PMDA) and citric acid (CA). The nanosponges were mechanically size-reduced via homogenization and ball milling, and characterized by FTIR, TGA, dynamic light scattering (DLS), and zeta potential measurements. Swelling kinetics, cross-linking density (determined using Flory–Rehner theory), rheological behavior, and mucoadhesion were evaluated under simulated gastric and intestinal conditions. The β-CD:PMDA 1:4 NS was selected for drug studies due to its optimal balance of structural stability, swelling capacity (~863% at pH 6.8), and highest apomorphine (APO) loading (8.23%) with 90.58% encapsulation efficiency. All nanosuspensions showed favorable polydispersity index values (0.11–0.30), homogeneous size distribution, and stable zeta potentials, confirming suspension stability. Storage at 4 °C for six months revealed no changes in physicochemical properties or apomorphine (APO) degradation, indicating protection by the nanosponge matrix. D-NS exhibited tunable swelling, pH-responsive behavior, and mucoadhesive properties, with nanoparticle–mucin interactions quantified by the rheological synergism parameter (∆G′ = 53.45, ∆G″ = −36.26 at pH 6.8). In vitro release studies demonstrated slow, sustained release of APO from D-NS in simulated intestinal fluid compared to free drug diffusion, highlighting the potential of D-NS as pH-responsive, mucoadhesive carriers with controlled drug release and defined nanoparticle–mucin interactions.

Phosphodiesterase 4 (PDE4) is a key enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), thereby regulating essential signaling pathways involved in inflammation and immune modulation. Structural studies have demonstrated a high degree of conservation within the catalytic domains of PDE4 isoforms, accompanied by subtle conformational variations that underlie their selectivity and tissue-specific distribution. Elucidating these structural features has been instrumental in guiding the rational design of PDE4 inhibitors. Although synthetic PDE4 inhibitors such as roflumilast and apremilast exhibit significant therapeutic efficacy, their clinical application is often limited by dose-dependent adverse effects. These effects primarily arise from insufficient isoform selectivity, as current inhibitors tend to target multiple PDE4 subtypes indiscriminately, resulting in off-target pharmacological actions and reduced tolerability. In contrast, natural products—including flavonoids, terpenoids, and related polyphenolic compounds such as curcumin, α-mangostin, and their derivatives—have emerged as promising molecular scaffolds. Their lower toxicity, favorable biocompatibility, and structural diversity enable fine-tuning of potency and selectivity through rational modification. Integrating structural insights derived from crystallographic and computational studies with the optimization of natural compounds offers a sustainable and effective strategy for the development of safer, isoform-selective PDE4-targeted therapies.

Oral drug delivery remains one of the most attractive routes for achieving safe, effective, and controlled therapeutic administration. Hydrogels represent promising systems for this purpose due to their biocompatibility, the versatility of natural and synthetic materials, and their tunable physicochemical properties. Among various candidates, dextrin-based hydrogels are particularly noteworthy, as they can respond to physiological gradients along the gastrointestinal tract, enabling targeted, site-specific, and sustained drug release for both localized and systemic treatments. This study aimed to synthesize and characterize dextrin-based hydrogels formulated from β-cyclodextrin (β-CD), KLEPTOSE® Linecaps (LC), and GluciDex®2 (GLU2) as building units, using citric acid (CA) and pyromellitic dianhydride (PMDA) as cross-linkers, for potential application in oral drug delivery systems. The obtained polymers displayed adjustable particle dimensions, pH-sensitive swelling characteristics, and an optimized cross-linking density, as calculated using the Flory–Rehner theory. Furthermore, rheological evaluations and mucoadhesion assays revealed pronounced viscoelastic behavior and strong adhesion to mucosal surfaces, confirming their suitability for oral drug delivery applications. Overall, these findings underscore the potential of dextrin-based hydrogels as mucoadhesive carriers for oral drug delivery, particularly in the treatment of neurodegenerative disorders, where they may facilitate drug transport across biological barriers and enhance therapeutic concentrations within the brain.

The CRISPR-Cas9 system has transformed biomedical research by enabling precise genetic modifications. However, efficient delivery of CRISPR components remains a major hurdle for therapeutic applications. To address this, we employed a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly) system to deliver an integrating GFP gene using the TILD-CRISPR method, which couples donor DNA linearization with RNP complexes. The physicochemical properties, loading efficiency, and cellular uptake of RNP with Ppoly were studied. After transfection, antibiotic selection and single-cell cloning were performed. Junction PCR was then performed on the isolated clones, and we compared the knock-in efficiency of Ppoly with that of the commercial CRISPRMAX™ reagent (Thermo Fisher, Invitrogen™, Waltham, MA, USA). The results demonstrate the encapsulation efficiency of over 90% for RNP and Ppoly, and cell viability remaining above 80%, reflecting the minimal toxicity of this approach. These attributes facilitated successful GFP gene integration using the TILD-CRISPR with RNP delivered via cyclodextrin-based nanosponges. The present method achieved a remarkable 50% integration efficiency in CHO-K1 cells, significantly outperforming the 14% observed with CRISPRMAX™ while maintaining lower cytotoxicity. This study highlights a promising platform for precise and efficient genome editing, with strong potential for therapeutic and regenerative medicine applications.

Cholesterol, the essential building block of cellular membranes, has proven to be a useful tool for increasing the biocompatibility and bioavailability of drug delivery systems in cancer treatment. Resveratrol, a natural polyphenolic compound with promising anticancer properties, faces significant limitations due to its low solubility and bioavailability, hindering its clinical utility. Therefore, in the present study, we aimed to design cholesterol-functionalized cyclodextrin nanosponges (Chol-NSs) with a tunable cholesterol content to optimize resveratrol encapsulation and delivery. Both formulations, free carbonyl diimidazole (CDI) NSs and functionalized Chol-NSs, demonstrated high drug loading and encapsulation efficiency. In vitro experiments revealed that cholesterol incorporation significantly improved the cellular uptake of nanocarriers and potentiated the cytotoxic effects of resveratrol on breast cancer cells. Importantly, both free CDI NSs and functionalized Chol-NSs, even at varying cholesterol percentages, demonstrated a safe profile against both fibroblast and breast cancer cell lines. These results indicate that cholesterol-functionalized nanosponges represent a promising platform for the effective and safe delivery of natural compounds in cancer therapy.