Over the past 30 years, carbon nanotubes have emerged as one of the most exciting classes of nanomaterials due to their unique physicochemical properties. While challenges in nanotube synthesis and processing initially hindered their adoption, many of these barriers have since been addressed by research and manufacturing advances, resulting in substantial industrial application of nanotubes across multiple sectors. However, much of this progress is not known in the academic community. This perspective discusses the current landscape and outlook of industrial integration of carbon nanotubes and key factors mediating widespread integration across all major material-related areas of human activity.

Few chemical methods controllably generate sp3 defects on single-walled carbon nanotubes, and fewer still create quantum wells that localize excitons and enhance near-infrared emission. Here we describe an aqueous, nanotube-catalysed Fenton reaction that enables the conjugation of an extensive range of small molecules lacking traditional single-walled carbon nanotube conjugation handles, generating quantum well defects with tunable electro-optical properties. We demonstrate the attachment of over 150 unique small molecules, including alcohols, amines, carbonyls, acrylates, amino acids and peptides. The resulting optical properties are governed by the electronic structure of the attached group, which determines the relative configuration of defects (ortho or para) within the graphitic lattice. Time-dependent density functional theory calculations confirm the assignment of the observed emission peaks to specific defect configurations. These molecularly driven effects enable precise control over the optical properties of the nanotubes, broadening the design space of rationally engineered quantum well-bearing nanomaterials.

Quantum well defect-modified single-walled carbon nanotubes are environmentally responsive nanomaterials with broad potential in biosensing, imaging, and quantum computing. The most widely used approach for their covalent functionalization relies on aryl diazonium chemistry, which introduces sp 3 -hybridized aryl defect sites onto the nanotube lattice. Here we investigate how solvent, pH, substituent electronics, and thermal annealing influence the functionalization of SWCNTs with aryl diazonium salts. This approach involves ‘over-functionalization’ with aryl groups resulting in loss of optical properties, followed by thermal annealing to reduce defect density. We find that solvent choice changes both the Raman D:G ratio and the relative intensity of E 11 , E 11 -, and, in some cases, E 11 *- emission. Thermal annealing at 200 °C under ambient atmosphere typically restores fluorescence from initially quenched samples, consistent with partial recovery from an overfunctionalized state. Finally, pH-dependent experiments suggest that electron-poor NO 2 PhN 2 -BF 4 reacts most effectively under acidic conditions, whereas electron-rich OMePhN 2 -BF 4 is more strongly activated under basic conditions. Overall, solvent and pH control the degree and optical outcome of aryl diazonium functionalization, while thermal annealing provides a practical post-reaction route for recovering useful defect emission from over-functionalized nanotubes. To our knowledge, this work provides the first systematic analysis of how solvent and pH govern quantum-well defect formation in aryl-functionalized SWCNTs.

Fibrotic remodeling of tissues and tumors establishes immune-suppressive microenvironments that drive organ dysfunction and, in cancer, limit responses to immunotherapy. Cells exhibiting features of cellular senescence are conserved drivers of fibrotic remodeling and thus represent therapeutic targets, yet senescent states are heterogeneous and can exert both beneficial and pathogenic effects, complicating therapeutic intervention. Here, we show that P-selectin is selectively expressed by subsets of senescent-like cells in fibrotic tissues and fibrotic tumor microenvironments. Leveraging fucoidan-based nanoparticles that bind P-selectin, we develop senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated cell states. SMNPs exhibit potent antifibrotic and immunomodulatory activity while markedly improving therapeutic index. Mechanistically, we identify a pathogenic, immune-suppressive macrophage population as a principal functional target of SMNPs in vivo. In fibrotic tumors, niche remodeling restores immune infiltration and sensitizes tumors to immune checkpoint-based therapies. More broadly, SMNPs establish a generalizable nanotherapeutic strategy for selectively targeting pathogenic senescent cell subsets across fibrotic disease and cancer.

Abstract Ependymoma (EPN) is the third most common malignant pediatric brain tumor. The most frequent and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children with a 5-year progression-free survival of 33%. In the absence of recurrent mutations, PFA EPN tumors are driven by EZHIP overexpression resulting in global loss of the gene repressive chromatin mark H3K27me3. Despite progress in EPN molecular characterization, the standard treatment remains surgery with adjuvant radiation therapy. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen using multiple drug libraries: (i) a 120 drug FDA-Approved Oncology collection (ODL3), (ii) a CTD2 Informer Set of 320 tool compounds, and (iii) a 336 drug Epigenetics Drug Collection on three patient-derived PFA-EPN cell lines. We found that these PFA-EPN cell lines were sensitive to several clinically relevant drugs, including those targeting epigenetic regulators. Multiple histone methyltransferase, JAK/STAT, proteasome, and BET domain inhibitors were also identified as high-value drug candidates. These results warrant further PFA-EPN functional evaluation in vivo, but dose-limiting toxicity and limited blood-brain barrier (BBB) penetration are known limitations for many of the identified compounds. To overcome these limitations, we are applying a novel P-selectin-targeted fucoidan-based nanoparticle technology recently shown as a viable approach for effective BBB drug penetration specifically at brain tumor sites in vivo. As proof of principle, we have successfully fucoidan-encapsulated BET domain inhibitor drugs including a BRD2/3/4 PROTAC degrader providing improved pharmacological properties. Our preliminary results show P-selectin expression on treatment-naive human PFA-EPN tumor vasculature with current studies underway to assess effects of radiation on P-selectin tumor vasculature expression enhancement as well as therapeutic assessment in PFA-EPN PDX mouse models. Collectively, these findings provide new putative therapeutic approaches in these rare yet aggressive tumors.

Abstract Medulloblastoma (MB) is the most common solid malignant brain tumor in children, with a five-year survival of ∼70-80%. Nevertheless, nearly ∼30% of patients experience recurrence, resulting in only 18% survival rate at three years. Although MRI can identify asymptomatic relapse, its clinical value is limited by low sensitivity, technical challenges, and associated sedation risks. MicroRNAs (miRNAs), small non-coding RNAs, remain stable in biofluids and may reflect tumor status and therapeutic response, making them strong biomarker candidates. We aim to detect early MB recurrence using a nanotechnology platform that rapidly and sensitively identifies biomarkers in vivo and from liquid biopsies ex vivo. Using a Sonic Hedgehog (SHH)-MB mouse model (Ptf1acre/+;Ptch1fl/fl), we profiled exosomal miRNAs from primary MB tissue explants and plasma. Members of the miR-17∼92 cluster and its paralogs were among the most highly secreted miRNAs in advanced SHH-MB explants, comprising the top 6% of ∼400 profiled miRNAs. Exosomal miR-17∼92 components were also present in MB patient plasma but not in healthy controls. MiR-19, a key cluster member, was detected in plasma from late-stage SHH-MB mice and was the only miRNA significantly associated with progression from early hyperplasia to advanced MB, with levels declining after radiation treatment. Our prior work has shown that single-walled carbon nanotube (SWCNT) nanosensors can detect local miR-19 across multiple biofluids, supporting its use as a recurrence biomarker. We are developing a hydrogel-encapsulated SWCNT optical nanosensor for non-invasive, longitudinal detection of miR-19 (or other miRNAs) hybridization events. This nanosensor can be implanted into the resection cavity of SHH-MB mice to enable non-invasive monitoring of local tumor recurrence through in vivo miR-19 detection. Members of the miR-17∼92 cluster, particularly miR-19, emerge as promising biomarkers for primary MB progression and potential recurrence. SWCNT nanosensors could provide a non-invasive approach for early MB detection.

Semiconducting single-walled carbon nanotubes (SWCNTs) are one-dimensional materials with unique photophysical and electronic properties, including environmentally sensitive near-infrared fluorescence. Their robust structure, resistance to photo-bleaching, and tunable fluorescence signatures based on chirality make them ideal for multiplexed sensing applications in monitoring pH, lipids, temperature, and analytes in cellular contexts. The covalent functionalization of SWCNTs introduces “color centers,” quantum well defects with distinct fluorescence emission, enhancing their environmental sensitivity and modifying fluorescence through structural defects. However, typical covalent modification of nanotubes is typically restricted to aryl defects and requires harsh conditions. We investigated novel functionalization methods for carbon nanotubes to produce color center nanotubes (CCNTs) have been developed, enabling the creation of advanced nanosensors with enhanced and customizable photophysical properties. Using a novel chemical approach under mild conditions, this research seeks to significantly expand the range of functionalized nanotubes by incorporating broad and diverse classes of molecules, including diverse biologically and chemically relevant compounds. The study focuses on elucidating the underlying reaction mechanisms through detailed kinetic and thermodynamic analyses, complemented by advanced characterization techniques. These insights guide the optimization of the functionalization process and allow for the precise design of nanotubes with tailored properties. Furthermore, the environmental sensitivity of these modified nanotubes was investigated by screening their responses to a panel of proteins, lipids, redox agents, and other biologically relevant molecules. The findings will support the development of a comprehensive library of nanosensors designed to monitor complex biological and chemical systems.

Although ferroptosis resistance is prevalent among many cancer cell types, precisely how ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that phospholipase PAFAH2 regulates ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized phospholipids in KEAP1 mutant and NRF2-active cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly ferroptosis state characterized by the enrichment of key phospholipids previously identified to be important in ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in ferroptosis induction and abrogation of ferroptosis resistance across cancer types.

Proteolysis-targeting chimeras (PROTACs) are catalytic protein degraders with promising preclinical activity. The clinical translation of PROTACs has been limited by poor pharmacologic properties and toxicities, in part due to their "non-druglike" characteristics, including large molecular weights. We found that the vast majority of PROTACs can self-assemble into nanoparticles, yielding nanoparticle PROTACs (nanoPROTACs) with ultrahigh drug loadings. While PROTAC molecular features can be deleterious to their pharmacokinetic properties, we found that they can drive nanoencapsulation more efficiently than FDA-approved small-molecule drugs. Using structure-based prediction algorithms, we identified spatial autocorrelation molecular descriptors that defined nanoPROTAC formation with 96% sensitivity at 100% specificity. NanoPROTACs, targeted to the tumor microenvironment via P-selectin, led to significantly enhanced tumor drug uptake, target degradation, tumor growth inhibition, and overall survival in solid tumor xenografts. These findings offer a broad strategy to improve the pharmacologic properties and therapeutic index of PROTACs and potentially other non-druglike experimental therapeutics.

The detection and identification of intracranial tumours is limited by the lack of accurate biomarkers and requires invasive biopsy procedures. We investigated a machine perception liquid biopsy approach to detect and identify intracranial tumours from peripheral blood and to discover biomarkers responsible for the predictions. Quantum well defect-modified single-walled carbon nanotubes stabilized with single-stranded DNA, interrogating 739 plasma samples from brain tumour patients, were used to train and validate machine-learning models to detect intracranial tumours with 98% accuracy and identify tumour type. The protein corona of the top model-contributing nanosensor was interrogated using quantitative proteomics, resulting in the identification of tumour ecosystem-secreted factors, both previously reported and newly discovered, originating from intracranial tumour cells, the tumour microenvironment and the innate immune system of patients with glioblastoma and meningioma. Newly discovered factors elicited linear nanosensor responses and were elevated in one or both tumour types, matching the original protein corona enrichment. This investigation reveals that a perception-based detection of disease in blood can identify biomarkers responsible for the signal and also amplify cancer detection signals by detecting factors beyond tumour cells, thereby recruiting the entire tumour ecosystem for cancer diagnosis.

Under controlled conditions, the covalent functionalization of semiconducting single-walled carbon nanotubes results in the formation of nanotubes with ‘color centers’ – emissive quantum well defects which fluoresce brightly in near infrared wavelengths. These ‘color center nanotubes’ (CCNTs) have highly tunable physical and chemical properties and environmental sensitivity, controlled via choice of both covalent and non-covalent modifications, such as choice of wrapping agent. CCNTs therefore have wide-ranging applications in bio-sensing, imaging, quantum computing and catalysis. We have developed new, rapid, scalable strategies for the synthesis of CCNTs, resulting in highly emissive defects. We have characterized the physical and chemical properties of these materials, and probed the underlying mechanisms of functionalization. We have investigated their sensitivity to various biologically relevant analytes, and explored their potential as highly controllable optical sensors with applications in diagnostics and analytical biochemistry.

Single walled carbon nanotubes (SWCNTs) exhibit environmentally sensitive fluorescence in the near infrared that can be leveraged to create sensors and diagnostics. Covalent functionalization of SWCNTs enhances their fluorescence emission by creating additional emission peaks. These new emission peaks provide additional sensitivity for sensor development. Existing synthesis methods for functionalized SWCNTs require long incubation times or harsh superacid reagents. We have uncovered a fast and easy method of SWCNT functionalization using hydrogen peroxide. This new reaction allows real time reaction monitoring allowing for high tunability of functional degree. Furthermore, it is compatible with different SWCNT wrappings as well as different functional groups, enabling the rapid generation of sensitive SWCNT sensors. We have applied this novel functionalization chemistry to create a sensor array for the detection of cytokine storm biomarkers.

Autophagy is a cellular process with important functions that drive neurodegenerative diseases and cancers. Lysosomal hyperacidification is a hallmark of autophagy. We developed an optical nanosensor technology that temporally and quantitatively monitors endolysosomal pH in live cells and in vivo, enabling the transient detection and spatial mapping of autophagy in vivo. The nanosensors are based on molecularly tunable fluorescent quantum defects on carbon nanotubes–whose near-infrared emission shifts quantitatively in response to local pH. The technology enabled novel biological measurements, including the dynamics of lysosomal acidification in cells and tumors upon autophagy-activating conditions, spatially and transiently within tumors in live mice. The technology enables non-invasive quantification of lysosomal pH, facilitating the long-term and in vivo monitoring of autophagy, and notably–measurements that can be compared between studies, because of the quantification. We anticipate that this work opens the door to quantum defects to facilitate additional discoveries in biomedicine.

Nanoparticles can improve drug pharmacokinetics, but low loading efficiencies can limit treatment efficacy. Drug-aggregation-based nanoparticles have demonstrated improved loadings of up to 90%, but few excipients facilitate efficient co-assembly. We investigated peptides as designer excipients because of their diverse chemical space and inherent biodegradability. We designed pentapeptide scaffolds to mimic the structure of known indocyanine excipients by modulating aromaticity, rigidity, and charge. We screened 184 formulations by using diverse drug cargoes. We found drug-peptide combinations that formed nanoparticles with up to 98% drug loading. Molecular dynamics simulations and mass spectrometry analysis demonstrated that tryptophan-drug interactions and solvent exposure of charged amino acid residues drove the formation of core-shell structures. Peptide-drug formulations containing the JAK2/FLT3 inhibitor lestaurtinib were investigated in acute myeloid leukemia models, resulting in enhanced anti-tumor efficacy. This work found that oligopeptides can be designed to efficiently co-assemble with therapeutic cargoes to result in high-loading nanoparticles that improve anti-tumor efficacy.

Objective: Radical therapies are associated with significant morbidity in patients with localized prostate cancer (PCa). While advances in nuclear magnetic resonance techniques have enabled the development of focal ablation procedures that can selectively destroy tumors, preserve the gland and surrounding structures, and minimize side effects, existing vascular-targeted photodynamic therapy (VTP) and nanodrug therapies often face limitations, such as recurrence and insufficient drug concentration at the tumor site. This study investigated a novel approach that combines VTP with systemic treatment using drug-loaded nanoparticles in a murine model, demonstrating substantial advancements beyond current monotherapies. Methods: SCID (severe combined immunodeficiency) mice were engrafted with androgen-sensitive prostate tumor cells (LNCaP-AR) and treated with a combination of VTP and two different drugs linked to fucoidan nanoparticles (Enzalutamide and Paclitaxel). Experiments were performed using different cohorts: the evaluation of oncological effect, the administration time and concentration of systemic therapy, a comparison of efficacy between VTP and radiotherapy, and the induction of the abscopal effect in untreated synchronous tumors. Results: The groups that received combination therapy showed better tumor control. After eight weeks, the recurrence-free survival rates were 87.5%, 62.5%, and 50% in the VTP + N-PAC, VTP + N-ENZ, and VTP monotherapy groups, respectively (p < 0.05). There was a significant difference in the intra-tumoral concentration of nanodrugs between the groups with combined treatment and monotherapy. After two weeks, the monotherapy groups showed almost total elimination of the drugs, whereas in the combined therapy groups, this concentration remained high, starting to decrease after three weeks (p < 0.05). Treatment with nanodrugs associated with VTP showed superior oncological benefits compared to radiotherapy alone or in combination with other therapies. The abscopal effect on synchronous tumors was not demonstrated with VTP alone or in combination with nanodrugs. Conclusions: Combining vascular photodynamic therapy with nanodrugs was highly effective in treating a prostate tumor model, leading to increased survival and a reduced risk of tumor recurrence. This approach significantly advances beyond existing VTP and nanodrug therapies by improving tumor control, ensuring sustained intra-tumoral drug concentration, and yielding superior oncological outcomes. Our results suggest that this therapy is a potential treatment option for prostate tumors treated with VTP in future clinical trials.

Synthesis methods of single walled carbon nanotubes (SWCNTs) result in mixtures of different chiralites. Chirality affects SWCNT diameter as well electronic and optical properties. For use in optical sensors, mono-chirality SWCNTs offer better signal compared to chirality mixtures. A common chirality separation method is aqueous two-phase extraction, where solutions of surfactants are used to partition SWCNTs based on chirality. The process results in a mono-chiral solution of SWCNTs wrapped in surfactant, however for sensing applications SWCNTs need to be exchanged from this surfactant wrapping to single stranded DNA wrapping. Concerns have been raised about residual surfactant remaining on the SWCNT surface after the exchange process and the effect this would have on the sensing capabilities of the SWCNT. To investigate this, we compared the emission spectra of covalently modified SWCNTs sonicated directly in DNA to that of SWCNTs exchanged from surfactant into DNA. We observed that emission from exchanged SWCNTs was red shifted compared to direct DNA sonicated SWCNTs, however exchanged SWCNTs had similar environmental responsivity to direct DNA sonicated SWCNTs.

INTRODUCTION: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Genetically, MB can be divided into four subgroups of which the SHH subtype histologically shows nodular architecture. Within this nodular architecture, there are islands of mature cells, with more abundant neuropil and a low proliferation rate, scattered among sheets of primitive cells. METHODS: We performed laser capture microdissection followed by whole transcriptome analysis, spatial transcriptomics using Digital Spatial Profiling, whole genome DNA methylation and ChIP-Seq analysis of mature and primitive areas from 8 medulloblastomas. We developed a genetically-engineered mouse model of SHH MB showing spontaneous maturation and lack of maturation with a conditional EZH2 genetic ablation or EZH2 overactivation respectively. Finally, we developed a fucoidan-based nanoparticle drug delivery across the blood brain barrier (BBB) for targeted molecular inhibition. RESULTS: Using whole transcriptome and DNA methylation analysis, we identified ∼120 differentially expressed genes between primitive and mature regions with enrichment for genes regulated by H3K4me3 and H3K27me3. ChIP-Seq analysis showed striking differences in H3K27me3 enrichment between primitive and mature medulloblastoma cells including at the EZH2 locus. Medulloblastoma specific EZH2 genetic ablation resulted in diffuse tumor cell differentiation and prolonged survival in mice (n = 10 per group, log-rank p = 0.01). Conversely, conditional EZH2 (Y641F) activation prevented medulloblastoma differentiation. A fucoidan-based nanoparticle successfully delivered the EZH2 inhibitor (EPZ-6438) across the murine BBB to achieve significant extension of mouse survival (median 70 days compared to 21 days in control mice; *p = 0.01, Mantel-Cox). CONCLUSIONS: Spontaneous maturation of medulloblastoma cells can be induced by inhibition of EZH2. Fucoidan-based nanoparticle delivery systems allows tumor specific targeted delivery across the BBB extending survival in mice.

Arrays of chemically modified and DNA-wrapped carbon nanotube-based nanosensors are powerful new tools for biomarker-independent diagnostics. When exposed to patient biofluids, an individual nanosensor can simultaneously interact with many different biological molecules, enabling the detection of collective molecular changes, constituting a “spectral fingerprint”, rather than measuring individual biomarkers. Biomolecule-nanosensor interactions result in quantitative changes in sensor emission that are employed by machine learning models as features to differentiate between sample categories, such as healthy versus disease. To determine the underlying molecular interactions responsible for changes in sensor emission, we conducted single-analyte titrations of biomolecules at physiologically relevant concentrations. Each sensor exhibited optical responses to multiple biological molecules, illustrating the ability of the nanosensors to concurrently interact with many biomolecules to detect subtle molecular shifts occurring in different disease states.

Fluorescence guided surgery (FGS) facilitates real time tumor delineation and is being rapidly established clinically. FGS efficacy is tied to the utilized dye and provided tumor contrast over healthy tissue. Apoptosis, a cancer hallmark, is a desirable target for tumor delineation. Here, we preclinically in vitro and in vivo, validate an apoptosis sensitive commercial carbocyanine dye (CJ215), with absorption and emission spectra suitable for near infrared (NIR, 650-900nm) and shortwave infrared (SWIR, 900-1700nm) fluorescence imaging (NIRFI, SWIRFI). High contrast SWIRFI for solid tumor delineation is demonstrated in multiple murine and human models including breast, prostate, colon, fibrosarcoma and intraperitoneal colorectal metastasis. Organ necropsy and imaging highlighted renal clearance of CJ215. SWIRFI and CJ215 delineated all tumors under ambient lighting with a tumor-to-muscle ratio up to 100 and tumor-to-liver ratio up to 18, from 24 to 168 h post intravenous injection with minimal uptake in healthy organs. Additionally, SWIRFI and CJ215 achieved non-contact quantifiable wound monitoring through commercial bandages. CJ215 provides tumor screening, guided resection, and wound healing assessment compatible with existing and emerging clinical solutions.

In this work we highlight the preclinical optimization of targeted tumor fluorophores for delineation. We utilize shortwave infrared fluorescence imaging (SWIRFI) under non-gated or filtered ambient lighting conditions to achieve a symbiotic fluorescence guided surgery ecosystem for unprecedented tumor contrast. With two commercially available targeted dyes we readily achieved tumor to muscle ratios in the ranges of 40 to 80, with exposure times as low as 1 ms within ANSI limited laser exposures. We highlight the metrics which can be used to quantify this contrast and signal, and further highlight the need for standardized metrics in academic and industry settings.