Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.

Aldose reductase (AKR1B1, EC: 1.1.1.21) is a recognized target for the treatment of long-term diabetic complications, since its activation in hyperglycemia and its role in the polyol pathway. In particular, the tissue-specificity of AKR1B1 expression makes the design of the traditional aldose reductase inhibitors (ARIs), and the more recent aldose reductase differential inhibitors (ARDIs), exploitable strategies to treat pathologies resulting from diabetic conditions. A brief overview of the roles and functions of AKR1B1 along with known ARIs and ARDIs was provided. Then, the design of the latest inhibitors in the scientific scenario was discussed, aiming at introducing the research achievement in the field of intellectual properties. In the end, patents dealing with AKR1B1 and diabetes filed in the 2019-2023 period were collected and analyzed. Reaxys, Espacenet, Scifinderⁿ, and Google Patents were surveyed, using 'aldose reductase' and 'inhibitor' as the reference keywords. The search results were then filtered by PRISMA protocol, thus obtaining 16 records to review. Although fewer in number than in the early 2000s, patent applications in the field of AKR1B1 inhibitors are still being filed, with a number of Chinese inventors reporting new synthetic ARIs in favor of the repositioning approach.

The oral cavity harbors an extensive array of over 700 microorganisms, forming the most complex biome of the entire human body, with bacterial species being the most abundant. Oral diseases, e.g. periodontitis and caries, are strictly associated with bacterial dysbiosis. Porphyromonas gingivalis and Streptococcus mutans stand out among bacteria colonizing the oral cavity. After a brief overview of the bacterial populations in the oral cavity and their roles in regulating (flora) oral cavity or causing diseases like periodontal and cariogenic pathogens, we focused our attention on P. gingivalis and S. mutans, searching for the last-5-year patents dealing with the proposal of new strategies to fight their infections. Following the PRISMA protocol, we filtered the results and analyzed over 100 applied/granted patents, to provide an in-depth insight into this R&D scenario. Several antibacterial proposals have been patented in this period, from both chemical - peptides and small molecules - and biological - probiotics and antibodies - sources, along with natural extracts, polymers, and drug delivery systems. Most of the inventors are from China and Korea and their studies also investigated anti-inflammatory and antioxidant effects, being beneficial to oral health through a prophylactic, protective, or curative effect.

Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1′ pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the µM range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.

Starting from the ADAMTS5/ADAMTS7 inhibitor EDV33, a structure-based optimization led to the lead compound 3a, with nanomolar activity against ADAMTS7 and good selectivity over ADAMTS5.

At the interface between chemistry and medicine, supramolecular assemblies are emerging as versatile platforms for therapeutic delivery. Their reversible non-covalent interactions and chemically tunable architectures allow the design of adaptive systems capable of transporting not only conventional small molecules, but also fragile biological macromolecules. In this context, gene therapy emerges as a transformative approach for cancer, metabolic disorders, and rare diseases, enabling modulation or correction of defective genes and gene products. However, the clinical translation of therapeutic nucleic acids, including miRNAs, anti-miRNAs, and related oligonucleotides, remains limited by poor membrane permeability, high hydrophilicity, large size, and rapid enzymatic degradation, requiring safe, biocompatible, and non-viral delivery systems. β-Cyclodextrin (β-CD) represents a privileged supramolecular building block for this purpose. Its hydrophobic cavity, hydrophilic surface, and derivatizable hydroxyl groups enable complex architectures, including first-generation β-CD-based nanosponges (NSs). These crosslinked polymeric systems combine host–guest inclusion, porous macromolecular organization, and opportunities for functional modification. In our design, bridge-like molecules (BLMs) based on cationic adamantyl derivatives can act as supramolecular connectors, promoting simultaneous interaction with the β-CD cavity and the anionic phosphate backbone of therapeutic nucleic acids. These modular platforms provide a proof of concept for supramolecular assemblies supporting nucleic acid delivery. Conceived for topical ocular administration, they may guide further optimization toward local or systemic applications in next-generation gene therapy.