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Rare cancers collectively account for a proportion of cancer-related morbidity and mortality, and patients face significant challenges, including delayed diagnosis, lack of targeted therapies, and poor clinical outcomes. Exosome-based therapies have emerged as promising tools to address these unmet needs. Exosomes, naturally secreted extracellular vesicles, are increasingly engineered as nanocarriers for the targeted delivery of chemotherapeutics, nucleic acids, and immune modulators. Their ability to modulate the tumor microenvironment, influence immune responses, and overcome drug resistance makes them especially attractive. In rare cancers, preliminary studies have demonstrated the utility of exosomes in improving tumor specificity, enhancing payload stability, and reducing systemic toxicity. Moreover, exosomes derived from tumor or immune cells can influence immune evasion, angiogenesis, and stromal remodeling, key processes in cancer progression. Despite this potential, the clinical application of exosome-based therapies in rare cancers remains underexplored. This review critically evaluates the limited but emerging body of evidence supporting exosome-based interventions in rare malignancies. By highlighting their therapeutic promise, we aim to understand exosome-driven strategies as personalized, effective, and accessible solutions for patients with rare cancers.

Recent studies have identified the mycobacterial adenosine triphosphate synthase inhibitor GaMF1 and its structural analogs as compounds with noteworthy antituberculosis activity. Despite these promising results, a significant limitation remains their cytotoxicity against human cells, which, in its current state, overshadows the therapeutic potential. Therefore, addressing this off-target toxicity is essential for the further development of these compounds as viable drug candidates. In this study, we systematically explored structural modifications of the original GaMF1 scaffold with the primary aim of reducing its inherent cytotoxicity. Individual regions of the parent structure were progressively replaced, enabling the identification of substituents that effectively attenuate cytotoxic effects. Importantly, these structural refinements also led to the emergence of pronounced antiparasitic activity, particularly against trypanosomal species such as Trypanosoma cruzi, Trypanosoma brucei brucei, and Trypanosoma brucei rhodesiense. These findings suggest that the biological potential of this compound class extends beyond what has previously been described. Furthermore, we evaluated the cytotoxicity of selected derivatives against a panel of tumor cell lines, where some compounds showed encouraging antiproliferative effects.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic treatments. This study evaluates the anticancer activity and mode of action of the copper(II) complex [Cu(HL¹)(NO₃)H₂O]·H₂O (CuHL¹), derived from (E)-N’-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide (H₂L¹), against a panel of TNBC cell lines (MDA-MB-231, MDA-MB-468, MDA-MB-157, HCC1806). CuHL¹ exhibits potent cytotoxicity in the low micromolar range (IC₅₀ ≈ 2 µM), surpassing cisplatin by up to 81-fold. In MDA-MB-231 cells, CuHL¹ inhibits colony formation and induced reactive oxygen species (ROS) generation in a concentration-dependent manner. Moreover, CuHL¹ triggers apoptosis as evidenced by Annexin V/PI staining and the modulation of Bax, Bcl-2, caspase-3, and cleaved caspase-3 protein levels. Label-free quantitative proteomics reveal 34 differentially expressed proteins, implicating pathways related to heat shock response, protein folding, lipid metabolism, and cell migration. Notably, CuHL¹ downregulates BCAR3, AJUBA, MPZL1, TP53, FASN, and HMGCS1, suggesting inhibition of prometastatic and lipid biosynthetic processes. Functional assays confirm reduced migratory capacity in MDA-MB-231 cells. These findings position CuHL¹ as a promising candidate for TNBC therapy, meriting further in vivo evaluation.

The Tres Cantos Antimalarial Set (TCAMS) library is a valuable resource for identifying hits for the antimalarial pipeline. We used principal component analysis (PCA) to explore this tranche of chemical space. Applying a set of 17 two-dimensional (2D) molecular descriptors, the chemical space was mapped in 2D PC space. Thereafter, the locations of known inhibitors and noninhibitors of synthetic hemozoin (β-hematin) formation, a well-established drug target during the asexual blood stage of the Plasmodium falciparum parasite life cycle, were superimposed onto the 2D map and counted. Within the +PC1, −PC2 quadrant, an area of enrichment emerged that could be used to predict the activity of test compounds. A subset of 861 TCAMS compounds (45 inhibitors and 816 noninhibitors) yielded a 27% hit rate when filtered using the enrichment map. Thereafter, 81 diverse compounds with predicted activity were purchased and 20 (25%) were active. B37, which contains a pyrido carbazole scaffold, demonstrated potent β-hematin formation inhibitory activity (IC₅₀ = 6.4 ± 0.19 μM) as well as noteworthy activity against the chloroquine-sensitive NF54 strain (IC₅₀ = 0.32 ± 0.03 μM). The PCA enrichment map for β-hematin inhibition is a useful tool for rapid identification of potential hit compounds and may be extended in the future to other antimalarial targets.

Using a combination of molecular docking and machine learning, the BioVision Protein Kinase Inhibitor library was screened for potential inhibitors with dual activity against two Plasmodium falciparum targets, β-hematin (synthetic hemozoin) formation and cGMP-dependent protein kinase (PfPKG). Three compounds with promising activity against both targets were identified. Derazantinib is the most potent hit compound with IC₅₀ values of 88 µM for inhibition of β-hematin formation (compared to 22 μM for chloroquine) and 0.160 µM against PfPKG. Pazopanib (β-hematin IC₅₀: 219 µM and PfPKG IC₅₀: 0.330 µM) and afatinib (234 and 2.61 µM, respectively) showed more moderate activity profiles against both targets.

In this study, a targeted and stimulus-responsive drug delivery system was designed and modeled for enhanced cancer therapy. Paclitaxel (PTX) release was investigated from trastuzumab-decorated SPION-loaded niosomes (TTSNs) integrated within polycaprolactone/chitosan electrospun fibers at varying TTSN concentrations (0%, 1%, 2.5%, and 5%) under both conventional and alternating magnetic field (AMF) conditions. The system was characterized using DLS, zeta potential, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, EDX, and swelling analyses, while MTT assays assessed cytocompatibility. The TTSNs exhibited a spherical morphology with a mean size of 221 nm and a zeta potential of −14.7 mV. The resulting nanofibrous mats displayed smooth, uniform fibers with an average diameter of 200 nm. Incorporation of TTSNs did not alter fiber morphology but increased the swelling capacity. Drug release studies revealed that exposure to AMF significantly enhanced PTX release, particularly in mats containing 5% TTSNs, indicating a clear magneto-responsive behavior. Korsmeyer–Peppas modeling provided the best fit for PTX release profiles both with and without AMF. The release mechanism and model fitting varied with TTSN concentration, emphasizing the importance of optimizing nanoparticle content for specific therapeutic applications.

Glioblastoma (GB) is the most common and aggressive malignant brain tumor, with a median survival of only 12–15 months despite current treatments with surgery, radiotherapy, and temozolomide (TMZ). Although TMZ induces cytotoxic DNA methylation in tumor cells, its efficacy is often limited by resistance mechanisms. To overcome these limitations, alternative therapeutic strategies—such as targeting the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway with MEK inhibitors like trametinib and selumetinib—are being explored. However, their clinical success is currently hindered by inadequate delivery across the blood–brain barrier and dose-limiting toxicity. Nanoparticles, particularly positively charged systems, offer enhanced cellular uptake and therapeutic performance due to their strong interactions with negatively charged cell membranes. Cyclodextrin (CyD)-based polymers are promising systems owing to their low toxicity and ability to form inclusion complexes with drugs. In this work, we investigate two cationic CyD polymers as potential nanocarriers for GB therapy based on trametinib and selumetinib. Their multivalent architecture and positive charge can facilitate both the encapsulation of drugs and membrane interactions. These systems present promising candidates for enhancing the efficacy of GB treatment.

δ-Lactones are structurally diverse natural products broadly distributed across plants, fungi, microbes, and marine organisms. Their six-membered cyclic ester scaffold, often embedded in polyketide, terpenoid, fatty acid-derived, or hybrid frameworks, underpins wide-ranging pharmacological activities, including cytotoxic, antimicrobial, antiparasitic, and anti-inflammatory effects as well as modulation of enzymes and signaling pathways. Clinically relevant examples such as lovastatin, the first FDA-approved statin, and artemisinin, a cornerstone antimalarial, highlight the therapeutic value of δ-lactone motifs. In contrast, fostriecin and leptomycin B, though unsuccessful in the clinic, inspired analog development and validated new biological targets. Recent advances in synthesis—including ring-closing metathesis, CH lactonization, asymmetric annulations, and biomimetic approaches—have streamlined access to complex δ-lactones, enabling stereocontrolled synthesis and structure–activity relationship studies. This review provides a comprehensive overview of bioactive natural δ-lactones, organized by biosynthetic origin, and emphasizes their structural diversity, biological functions, and synthetic accessibility.

Antibody-drug conjugates (ADCs) that equip multiple cytotoxic drugs on an antibody have been developed, particularly in cancer chemotherapy. In the treatment of viral infectious diseases, there are dominantly fewer examples of ADCs. Recently, we developed double-warhead ADCs targeting the entry of human immunodeficiency virus type 1 (HIV-1) into host cells. One is a small molecule CD4 mimic, which is a competitive inhibitor against the interaction between a viral envelop protein, gp120, and a primary receptor, CD4, and the other is neutralizing antibodies, which recognize the regions of gp120, exposed by its conformational change after the interaction between gp120 and CD4. The conformational changes are also triggered by the binding of gp120 and a CD4 mimic, and therefore, the ADCs show positive effects on anti-HIV-1 activity compared to the combinational use of CD4 mimics with neutralizing antibodies. Herein, we synthesized novel ADCs containing a CD4 mimic and a neutralizing antibody, KD-247, using tCAP chemistry, which is based on a site-specific modification method for IgG antibodies, and evaluated their anti-HIV-1 and antibody-dependent cellular cytotoxicity (ADCC) activities. As a result, the KD-247-adopted ADCs demonstrated enhanced anti-HIV-1 activities, whereas all of the ADCs reduced their ADCC activities.

Antibacterial photodynamic therapy (aPDT) is a promising strategy for combating prevalent antibiotic-resistant bacteria. However, development of efficient aPDT agents that can simultaneously eradicate resistant pathogens within biofilms and host cells with good biocompatibility remains a big challenge. Herein, three novel D–D-π-A–A type dyes (TPATA, TPATC, and TPATPy) were designed and synthesized. TPATPy can efficiently produce reactive oxygen species (ROS) mainly through type I mechanism, which is beneficial for overcoming hypoxia within biofilms. Besides, introduction of pyridinium cations in TPATPy enhances the binding ability with negatively charged bacteria and biofilms through electrostatic interactions. Therefore, TPATPy not only exhibited excellent aPDT activity toward planktonic bacteria, but also destroyed mature biofilms and the embedded pathogens. Moreover, TPATPy could selectively and efficiently photo-inactivate intracellular methicillin-resistant Staphylococcus aureus (MRSA), being more potent than vancomycin. So far as we know, TPATPy should be the first example that can simultaneously eradicate intractable pathogens within biofilms and host cells. The efficacy and safety of TPATPy in accelerating wound healing have also been demonstrated in an MRSA-infected skin wound model in mice. These results may provide new ideas for developing multifunctional aPDT agents to solve the intractable problems in antibacterial treatment.