Terasaki Foundation

Abstract Isocitrate dehydrogenase-mutant (IDHmut) gliomas are a distinct subset of diffuse gliomas in younger adults, including WHO Grade 2–3 oligodendrogliomas and astrocytomas, as well as a subset of Grade 4 astrocytomas. The recent INDIGO trial demonstrated the efficacy of Vorasidenib (Vora), a targeted mIDH inhibitor, in non-enhancing, treatment-naïve, low-grade (Grade II) IDHmut gliomas, leading to FDA approval in August 2024. However, nearly one-half of patients in the trial demonstrated progression at ~20 months and response rates in MRI contrast-enhancing and/or high-grade gliomas remain limited. This underscores the urgent need to (1) understand sensitivity and resistance mechanisms to Vora and (2) develop salvage therapies for a broader range of IDHmut glioma patients. A major obstacle is the scarcity of clinically relevant, patient-derived IDHmut models, particularly from low-grade gliomas. To address these limitations, we developed NanoGlio, a nanoliter-volume organoid platform, enabling rapid generation of patient-derived IDHmut glioma models and assessment of Vora sensitivity within 14-21 days. We established NanoGlio cultures from five Grade 2, one Grade 3, and four Grade 4 IDHmut cases—three with both enhancing and non-enhancing regions—as well as five IDH wild-type controls. Growth and morphology in NanoGlio varied by WHO grade: low-grade tumors grew slowly with lower cellularity, while high-grade IDHmut tumors proliferated rapidly. Vora induced morphological changes in low-grade and non-enhancing high-grade organoids but increased proliferation in enhancing high-grade organoids. Bulk RNA sequencing showed that NanoGlio recapitulates 15 of the top 20 pathways altered in clinical IDH inhibitor trials, with trends in gene expression changes closely mirroring those observed in patient samples. Vora treatment induced upregulation of neural function- and tumor suppression-associated genes, such as NPTX1, SPOCK2, SEZ6, NR1D1, OPCML and SNAP25, in IDHmut organoids. Future work will incorporate single-cell RNA sequencing to refine differentiation trajectories and uncover resistance mechanisms.

Abstract Primary central nervous system lymphoma (PCNSL) is a lethal cancer with poor survival, especially in its recurrent form. This is mainly due to low penetrance of therapeutic agents across the blood brain barrier (BBB). We created a novel nano immunodrug (nanodrug) that can cross the BBB and deliver anti-cancer agents directly to the tumor. The RNA therapeutics based on N-(2-hydroxypropyl)methacrylamide copolymer nanoplatform that was designed to block lymphoma’s cell c-Myc protein synthesis and to ensure brain tumor targeting and BBB crossing. Inhibiting of c-Myc protein synthesis played a dual role as anti-tumor proliferative factor and immune stimulator. Angiopep-2 peptide is conjugated to the nano platform to provide BBB crossing and brain lymphoma cell targeting via LRP-1 receptor. The nanodrug also contains H6 (6 histidines for endosome escape) to release into lymphoma cell cytoplasm. We tested the nanodrug in a A20 intracranial brain lymphoma mouse model alone, and in combination with anti-PD-1 antibody. Treatment with nanodrug resulted in a significant survival advantage compared to control. Survival was significantly enhanced when the nanodrug was co-injected with anti-PD-1. Spectral flow cytometry and RNA-seq analysis of treated tumors showed robust activation of tumor-infiltrating T lymphocytes with enhanced interferon γ signaling and polarization to M1-type macrophages. Artificial Intelligence-assisted analysis of gene expression data from RNA-seq revealed novel immune pathways, molecular targets, and suggested effective multifunctional drugs. Overall, we created a novel nano therapeutic drug delivery system that inhibits tumor c-Myc protein to treat PCNSL. When used in conjunction with anti-PD-1 checkpoint inhibitor, the treatment results in enhanced survival of tumor bearing animals by activating both adaptive and immune responses. SUPPORT NIH grants: R01 CA246716, R01 CA206220, R01 CA209921, R01 CA284247

Carbon‐based nanomaterials (CBNs), including graphene oxide (GO), carbon nanospheres (CNSs), carbon nitrides (CNs), carbon nanotubes (CNTs), carbon dots (CDs), nanoporous carbon, and nanocomposites, possess exceptional thermal, mechanical, electrical, and optical properties with highly versatile surface chemistries. Their tunable size, shape, and surface functionalities facilitate strong π–π interactions and semiconductor‐like behavior, enabling efficient light absorption and intimate biomolecular interfacing. These attributes have positioned CBNs as leading candidates in biomedical engineering, inspiring biomimetic designs that integrate organic and inorganic functions within unified architectures. This review highlights recent advances in the use of CBNs for next‐generation biosensing and theranostics. Approaches such as physicochemical engineering, deoxyribonucleic acid (DNA) origami templating, peptide‐ or enzyme‐assisted assembly, polysaccharide anchoring, and lipid modification have enhanced their biocompatibility, selectivity, and catalytic activity. Innovations in fluorescence switching, aptamer–CNT photophysics, and spacer‐controlled energy transfer enable ultra‐sensitive detection of metal ions, metabolites, neurotransmitters, pathogens, drugs, and cancer biomarkers. Furthermore, integrated CBN‐based platforms, including field‐effect transistors and laser‐scribed graphene electrodes, demonstrate capabilities for single‐virus or single‐cell diagnostics and responsive therapeutic intervention. Finally, translational challenges related to scalable synthesis, biosafety, regulatory harmonization, and public acceptance are discussed, and interdisciplinary strategies combining flexible electronics, organ‐on‐chip models, and AI‐guided design to advance clinical translation of CBN‐enabled precision diagnostics and personalized theranostics are proposed.

In this review, we explore key innovations in photoactivated therapeutic programming of carbon-based nanomaterials (CBNs), focusing on their diverse nanostructural configurations and their exceptional photothermal, photochemical, and photoacoustic properties. These attributes position CBNs as remarkable phototherapeutic agents, capable of addressing critical challenges in targeted cancer therapy through their precision, multifunctionality, and adaptability to specific therapeutic modalities. We will explore their diverse derivatives, and the role of chemical augmentation and site-specific surface functionalisation, which are pivotal in optimising the targeting and efficacy of phototherapeutic interventions. The biological and physical relevance of this ever-growing library of nanomaterials in targeted phototherapy will be thoroughly explored. Dynamic photo-triggering of the underlying molecular mechanisms of action e.g., energy conversion modalities lie at the heart of these therapeutic innovations. We will further discuss the tunability and programming of these carriers and structure-function alterations at specific therapeutic wavelengths. The application space of phototherapies is thoroughly mapped exploring the three primary approaches of photothermal therapy, photodynamic therapy and photochemical internalisation as well as emerging techniques and promising multimodal approaches that combine two or more of these processes. The specificity of the target tissue site and the approach under study forms another critical focus area of this review, with an emphasis on three types of cancer-breast cancer, lung cancer, and gliomas-that have demonstrated some of the most promising outcomes from photomedicine. We also provide a perspective on in vitro and in vivo validation and preclinical testing of CBNs for phototherapeutic applications. Finally, we reflect on the potential of CBNs to revolutionise targeted cancer therapy through data-driven materials design and integration with computational tools for biophysical performance optimisation. The exciting integration of machine learning into nanoparticle research and phototherapy has potential to fundamentally transform the landscape of nanomedicine. These techniques ranging from supervised learning algorithms such as random forests and support vector machines to more advanced neural networks and deep learning, can enable unprecedented precision in predicting, optimising, and tailoring the properties of nanoparticles for targeted applications. The transformative impact of photoactivated CBNs in advancing cancer treatment, paves the way for their clinical application and widespread adoption in personalised photomedicine. We conclude with a section on the current challenges facing the reproducibility, manufacturing throughput, and biocompatibility of these nanostructured materials including their long-term effects in trials and degradation profiles in biological systems as evaluated in vitro and in vivo.

Burn wounds are a common traumatic injury that impair cellular function and hinder the healing process, often resulting in significant skin loss. While autologous skin grafting is considered the gold standard for treating burns, its widespread use is limited due to donor site morbidity and the requirement for large amounts of tissue. Traditional wound dressings and treatments often fail to ensure complete recovery. Being initially FDA-approved to treat multiple sclerosis, 4-aminopyridine (4-AP) has also been shown to accelerate burn wound closure by transforming keratinocytes and fibroblasts when administered systemically. However, prolonged systemic use of 4-AP can lead to significant side effects. In this study, we aimed to repurpose 4-AP for treating skin burn wounds by delivering it topically using a laponite-gelatin gel formulation. This method allows for non-invasive and localized drug delivery on burn wound site. We evaluated the physical properties of the 4-AP gel shear thinning behavior, drug release kinetics, biocompatibility, and functional wound closure using a scratch assay. Moreover, our in vivo experiments showed that the 4-AP loaded gel accelerates wound healing by enhancing re-epithelialization and hair follicle regeneration and promoting fibroblast to myofibroblast transformation, which supports extracellular matrix remodeling after skin burns. This novel application of the 4-AP gel could offer a promising alternative to current burn wound therapies, potentially leading to improved outcomes for burn patients.