High-grade gliomas are devastating cancers with dismal prognosis, largely because current chemotherapeutics fail to cross the blood–brain barrier and lack tumor-cell specificity. Nanotechnology aims to overcome these limitations through targeted drug delivery. Here, a quadruple-conjugated nanomodel was synthesized using carbon dots (C-dots) as biocompatible nanocarriers via a one-pot reaction that covalently links two targeting peptides and two anticancer agents. The short peptide (shPep-1) targets the tumor-restricted receptor IL13Rα2, whereas the long peptide (lnPep-1) contains a nuclear localization signal for enhanced intracellular trafficking. Therapeutic cargo consists of epirubicin and the temozolomide metabolite 5-aminoimidazole-4-carboxamide. This nanomodel displays potent cytotoxicity in multiple high-grade glioma cell lines at 50 nM while remaining relatively non-toxic to normal cells (IC₅₀ > 2 µM). Despite a lower drug-loading capacity than single-peptide formulations, it induced greater glioma cell death, underscoring the enhanced therapeutic synergy of its dual-peptide, dual-drug design. Fluorescence studies confirm superior uptake and nuclear delivery, establishing C-dots as a stable, cost-effective, modular platform for next-generation personalized cancer nanotherapies. Carbon dots can serve as drug delivery systems, enhancing drug solubility, bioavailability and accumulation within tumours while reducing off target effects. Here, the authors report a quadruple-conjugated nanomodel consisting of two targeting peptides and two anticancer agents using carbon dots as nanocarriers, demonstrating its cytotoxicity in multiple high-grade glioma cell lines.

Glioblastoma (GBM) is an aggressive primary brain tumor with a median survival of 14–15 months even with standard multimodality treatments. The effectiveness of surgical resection, chemotherapy, and radiation therapy are limited by resistance mechanisms including tumor heterogeneity, immunosuppression, presence of stem-like cells, and inhibited drug delivery due to the blood–brain barrier (BBB). The BBB is composed of endothelial cells with tight junctions and selective transport systems, which prevent drug delivery to the tumor at therapeutic levels. Amino acid (AA) transporters have emerged as promising therapeutic targets for overcoming these limitations and enhancing GBM treatment. This review highlights the role of AA transporters in GBM, emphasizing their potential in enhancing targeted therapy, diagnosis, and disease monitoring. We summarize and discuss the 22 AA transporters which are upregulated in GBM, as well as those that demonstrate prognostic correlation. Among these, LAT1 (SLC7A5) has garnered the most attention for its role in drug delivery and imaging, while other transporters exhibit potential as diagnostic and therapeutic targets. Furthermore, nanoparticle technology has emerged as an innovative strategy to enhance targeted therapy through AA transporters. They can enable extended drug circulation, enhanced BBB penetration, and target-specific localization, offering synergistic therapeutic effects. This review emphasizes the importance of AA transporters as multifaceted tools for improving GBM treatment outcomes and the potential of combining AA transporter-targeted therapies with emerging technologies to address the limitations of current GBM management strategies.

Background: Spondylolisthesis and spondylolysis are common causes of chronic low back pain. When conservative treatments fail, lumbar spinal fusion is often the recommended surgical option. This article presents a novel approach to spinal fusion for vertebral misalignment in spondylolisthesis, utilizing mallet manipulation after implant anchoring to correct vertebral slippage during anterior lumbar interbody fusion (ALIF). Methods: We describe two male patients, aged 55 and 61, both with severe back pain caused by grade II spondylolisthesis at L5-S1. The second patient also had grade I spondylolisthesis at L4-L5. Failing conservative treatment, both patients required surgical intervention. The patients underwent a two-level ALIF at L4-L5 and L5-S1. For segments with anterior slippage of the vertebral body, the technique involved placing two screws into the upper vertebral body to partially secure the implant position. With the holder attached to the implant and anchored into the upper vertebral body, the segment was advanced by tapping the holder with a mallet until satisfactory alignment was achieved. An awl was then advanced into the vertebral body below, followed by placement of a fixation screw. Fusion was finalized using posterior pedicle screw fixation with O-arm navigation in a minimally invasive percutaneous fashion. Results: Both patients did well post-operatively. At an 8-week post-op exam, imaging showed a healing 2-level fusion with complete correction of their anterior slippage. The patients also reported no back pain. Conclusion: This article demonstrates the feasibility of a novel mallet/holder manipulation technique during an ALIF, aimed at reducing anterior slippage in patients with spondylolisthesis.

The prognosis for patients diagnosed with glioblastoma remains dismal with an average survival of about 15 months. Recently, it has been shown that glioblastoma stem-like cells (GSCs) drive tumor progression and are responsible for tumor regrowth following treatment; therefore, successful elimination of this cell population is necessary for disease eradication. Methoxy substituted chalcones have demonstrated anti-cancer effects with diverse molecular mechanisms. In this study, we synthesized 24 methoxy containing compounds, including 5 novel compounds, and tested their cytotoxicity toward 3 GSC lines and 2 non-tumor cell lines. We identified 13 compounds demonstrating an average GSC IC50 value below 10 mu M, many of which were less toxic to the noncancer cell lines. In silico reverse screening identified probable targets for 7 out of the 13 active compounds. Some targets have been well-investigated such as the epidermal growth factor receptor; however, others such as 17beta hydroxysteroid dehydrogenase type 3 warrant further study.

In this new study, we present an intriguing development in the field of theranostics: the simplistic self-assembly of red-emissive amphiphilic porphyrin-like carbon dots (P-CDs). By harnessing their exceptional photophysical properties, we have revealed a strong candidate as the ideal photosensitizer (PS) for applications, particularly in the realm of imaging. Spanning a remarkable size average between 1-4 nm, these particles exhibit both highly stable and unparalleled emission characteristics between 650 and 715 nm in water in comparison to current carbon dots (CDs) available. Lastly, these CDs were fairly non-toxic when tested against normal human cell lines as well as were found to have favorable imaging capabilities in zebrafish embryo.

Over time, the interest in developing stable photosensitizers (PS) which both absorb and emit light in the red region (650 and 950 nm) has gained noticeable interest. Recently, carbon dots (CDs) have become the material of focus to act as a PS due to their high extinction coefficient, low cytotoxicity, and both high photo and thermal stability. In this work, a Federal and Drug Association (FDA) approved Near Infra-Red (NIR) organic fluorophore used for photo-imaging, indocyanine green (ICG), has been explored as a precursor to develop water-soluble red emissive CDs which possess red emission at 697 nm. Furthermore, our material was found to yield favorable redimaging capabilities of glioblastoma stem-like cells (GSCs) meanwhile boasting low toxicity. Additionally with post modifications, our CDs have been found to have selectivity towards tumors over healthy tissue as well as crossing the blood-brain barrier (BBB) in zebrafish models.

Carbon dots (CDs) from glucose were synthesized using two of the most common bottom-up methods, namely, microwave assisted (MW) and hydrothermal carbonization (HT). Synthetic parameters such as reaction time, temperature, and precursor concentration were changed to study the effects of each parameter on CD size, structure, surface functionalities, charge, photoluminescence behavior, quantum yield, cytotoxicity, blood–brain barrier (BBB) crossing ability and bioimaging. A detailed analysis is performed to compare the structure and properties of the CDs synthesized in ten different conditions. We show that the synthesis route drastically changes the structure, properties, and related functions of glucose-derived CDs yielding two different subtypes of CDs. Surprisingly, CDs that was synthesized via HT method showed specific anticancer activity against a neuroblastoma cell line while being non-toxic towards healthy cell lines, indicating significant potential for therapeutic applications. CDs synthesized via MW crosses the BBB in zebrafish and rat models, and accumulates in neurons. CDs synthesized via MW method showed high biocompatibility and a great potential to be used for bioimaging applications in vitro and in vivo targeting neurons. Finally, a formation mechanism of CDs is proposed for both HT and MW synthesis routes.

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood–brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and micellar molecules of varying structures and compositions, have been investigated as a potential therapy to circumvent some of these inherent challenges. Carbon dots (CDs) have recently gained popularity as a novel nanoparticle with theranostic properties. This carbon-based modality is highly modifiable, allowing for conjugation to drugs, as well as tumor-specific ligands in an effort to more effectively target cancerous cells and reduce peripheral toxicity. CDs are being studied pre-clinically. The ClinicalTrials.gov site was queried using the search terms: brain tumor and nanoparticle, liposome, micelle, dendrimer, quantum dot, or carbon dot. At the time of this review, 36 studies were found, 6 of which included pediatric patients. Two of the six studies investigated nanoparticle drug formulations, whereas the other four studies were on varying liposomal nanoparticle formulations for the treatment of pediatric brain tumors. Here, we reviewed the context of CDs within the broader realm of nanoparticles, their development, promising pre-clinical potential, and proposed future translational utility.

Abstract The unfolded protein response (UPR) is a pro-survival mechanism triggered by cellular stresses encountered by tumor cells, such as hypoxia, acidosis, reactive oxygen species and even radiation and chemotherapy. In response to increased unfolded or mis-folded proteins in the endoplasmic reticulum (ER), the UPR initiates specific cell signaling pathways aiming to alleviate ER stress and restore ER proteostasis which include increasing the expression of chaperones to aid in protein folding, enhancing protein degradation and reducing global protein synthesis. However, if homeostasis cannot be restored, the UPR switches from survival to cell death. The UPR is a relatively novel therapeutic target for glioblastoma (GBM), and specifically GBM stem-like cells (GSCs) which maintain tumor heterogeneity, drive GBM tumor growth and therapy resistance. Here we tested a series of curcumin derivatives against three GSC lines and identified a trimethoxy bis-chalcone which promotes robust GSC death with an average IC50 of just below 300 nM, a 100-fold increase in activity compared to curcumin. Furthermore, this bis-chalcone was non-toxic to normal human mesenchymal stem cells. Western blot analysis indicated that the bis-chalcone induced robust activation of UPR pro-death protein C/EBP Homologous Protein (CHOP) while simultaneously decreasing the expression of pro-survival chaperone GRP78/Bip. Lastly our bis-chalcone induced caspase 7 expression and PARP cleavage indicating apoptosis. Most ER stress inducing agents promote both the survival, upregulation of Grp78, and cell death arms of the UPR. Here we identified a compound that only promotes UPR cell death signaling and is highly toxic to radiation and temozolomide resistant GSCs while demonstrating no toxicity to non-tumor cells. This is a promising lead compound for the development of UPR targeted GSC/GBM therapeutics.

High-grade gliomas remain among the most lethal neoplasms. Nanotechnology aims to Improve drug targeting and efficacy. Here we developed a quadruple nano-model (QNM) that specifically targets pediatric high-grade glioma cells and delivers chemotherapies to the cell nucleus. This carbon dot based QNM were fabricated by covalently attaching two drugs (epirubicin and temozolomide) and two targeting peptides. ShPep-1 peptide binds to the IL-13Rα2 receptors allowing for cellular import while lnPep-1h peptide delivers the DNA damaging drugs to the nucleus. Despite demonstrating the lowest measurable drug content (23.3%), the dual peptide linked QNM induced significantly greater cell death than single peptide linked conjugates suggesting enhanced cell uptake. Greatest effect was observed in glioblastoma (SJ-GBM2) and diffuse intrinsic pontine glioma (NP53) cells with IC50s of approximately 60 nM, 3-6-fold lower than single peptide conjugates. Imaging studies using FITC-conjugated carbon dots confirmed the dual peptide conjugate demonstrated greatest cellular uptake and nuclear localization.

High-risk neuroblastoma (NB) portends very poor prognoses in children. Targeting tumor metabolism has emerged as a novel therapeutic strategy. High levels of nicotinamide-adenine-dinucleotide (NAD+) are required for rapid cell proliferation. Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme for NAD+ salvage and is overexpressed in several cancers. Here, we determine the potential of NAMPT as a therapeutic target for NB treatment. NAMPT inhibition cytotoxicity was determined by trypan blue exclusion and LDH assays. Neuroblastoma stem cell self-renewal was evaluated by neurosphere assay. Protein expression was evaluated via Western blot. The effect of targeting NAMPT in vivo was determined using an NB1691-xenografted mouse model. Robust NAMPT expression was demonstrated in multiple N-MYC amplified, high-risk neuroblastoma cell lines. NAMPT inhibition with STF-118804 (STF) decreased ATP, induced apoptosis, and reduced NB stem cell neurosphere formation. STF treatment down-regulated N-MYC levels and abrogated AKT activation. AKT and glycolytic pathway inhibitors in combination with NAMPT inhibition induced robust, greater-than-additive neuroblastoma cell death. Lastly, STF treatment blocked neuroblastoma tumor growth in mouse xenograft models. NAMPT is a valid therapeutic target as inhibition promoted neuroblastoma cell death in vitro and prevented tumor growth in vivo. Further investigation is warranted to establish this therapy's role as an adjunctive modality.

Abstract Ultimate goal of the nanomedicine is built on the idea of robust targeted delivery of complex assemblies that contain sufficient amount of multiple therapeutics and diagnostic agents for highly localized payload release with no adverse side effects. Besides the numerous efforts on the field of cancer specific nanomedicine, still there is a great need for improvements in terms of target specificity. Previously, we have reported a target-specific carbon dots- based dual nano-drug delivery system. In study, for the first time in literature, surface functional group of the carbon dots were conjugated with four different ligands namely, two peptides (shPep-1 and lnPep-1) and two chemotherapeutic drugs (epirubicin and temozolomide). Here, we advanced our drug delivery system as a dual drug nano-carrier (quadruple nano-model) that explicitly targets the IL-13Rα2 receptors and the nucleus of high-grade glioma brain tumors. The successful conjugation of each molecule onto carbon dots (CDs) was meticulously characterized with numerous analytical techniques. Additionally, the in vitro cell viability assay revealed that quadrupole nano-model significantly reduced the cancer cell viability compared to the single peptide dual drug linked conjugates. Further, in vitro bioimaging studies using FITC conjugated single and dual peptides models, showed that dual peptide model exhibited greater FITC fluorescence throughout the cell including the nucleus compared to the single peptide models. This observation is evidence for improved cancer cell uptake and nucleus colocalization of quadrupole nano-model. Our quadrupole nano-model fully serves the ultimate goal of nanomedicine as a nanocarrier which contains two targeting peptides and two therapeutics simultaneously.

Background Dropped head syndrome (DHS) is a recently recognised cause of cervical spinal deformity and disability. The combination of Parkinson's disease (PD) and inflammatory myopathy in the genesis of DHS has not been previously reported. Furthermore, the optimal surgical treatment of progressive DHS remains undefined. Case description We report the case of a 64-year-old patient with severe DHS and coronal plane deformity secondary to underlying PD, precipitated by a focal paraspinal myositis, successfully corrected using asymmetric sternocleidomastoid (SCM) release and circumferential cervical fusion. The nuances of decision-making in this challenging patient population are highlighted, including the benefits of intraoperative traction, anterior column reconstruction and bicortical screw fixation. Postoperatively, significant reductions in pain and disability were achieved, along with restoration of cervical lordosis (CL), C2-7 sagittal vertical axis (CSVA) and chin-brow vertical angle (CBVA). Conclusions Circumferential cervical fusion with concomitant SCM release is a useful option in the treatment of recalcitrant DHS with biplanar deformity, addressing the unique biomechanical and endocrinological challenges posed by patients with underlying PD.

Carbon Dots (CDs) have recently attracted a considerable amount of attention thanks to their well-documented biocompatibility, tunable photoluminescence, and excellent water solubility. However, CDs need further analysis before their potential use in clinical trials. Previously, we reported a new type of carbon nitride dot (CND) that displayed selective cancer uptake traits attributed to structural resemblances between CNDs and glutamine. Here, the effects of surface structural differences on the cellular uptake of CNDs are further investigated to understand their selective cancer cell uptake trend. Beyond enhanced drug loading on modified CNDs, our cytotoxicity, western blotting and bioimaging studies proposed that modified CNDs' cellular uptake mechanism is thoroughly linked with ASCT2 and LAT1 transporters. Therefore, CNDs have a promising trait of selective cancer cell targeting by utilizing highly expressed transporters on cancer cells. Additionally, drug loaded CNDs exhibited improved anti-cancer efficacies towards cancer cells along with good non-tumor biocompatibilities.

The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4′-amino chalcones with the rationale that the amino group would serve as a “handle” to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4′-amino and 9 4′ derivatives) including 5 novel chalcones, and found that 13 had an IC50 below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology.

Neuroblastoma (NB) is a pediatric malignancy affecting the peripheral nervous system. Despite recent advancements in treatment, many children affected with NB continue to submit to this illness, and new therapeutic strategies are desperately needed. In recent years, studies of carbon dots (CDs) as nanocarriers have mostly focused on the delivery of anticancer agents because of their biocompatibility, good aqueous dissolution, and photostability. Their fluorescence properties, surface functionalities, and surface charges differ on the basis of the type of precursors used and the synthetic approach implemented. At present, most CDs are used as nanocarriers by directly linking them either covalently or electrostatically to drug molecules. Though most modern CDs are synthesized from large carbon macromolecules and conjugated to anticancerous drugs, constructing CDs from the anticancerous drugs and precursors themselves to increase antitumoral activity requires further investigation. Herein, CDs were synthesized using difluoromethylornithine (DFMO), an irreversible ornithine decarboxylase inhibitor commonly used in high-risk neuroblastoma treatment regiments. In this study, NB cell lines, SMS-KCNR and SK-N-AS, were treated with DFMO, the newly synthesized DFMO CDs, and conventional DFMO conjugated to black carbon dots. Bioimaging was done to determine the cellular localization of a fluorescent drug over time. The mobility of DNA mixed with DFMO CDs was evaluated by gel electrophoresis. DFMO CDs were effectively synthesized from DFMO precursor and characterized using spectroscopic methods. The DFMO CDs effectively reduced cell viability with increasing dose. The effects were dramatic in the N-MYC-amplified line SMS-KCNR at 500 μM, which is comparable to high doses of conventional DFMO at a 60-fold lower concentration. In vitro bioimaging as well as DNA electrophoresis showed that synthesized DFMO CDs were able to enter the nucleus of neuroblastoma cells and neuronal cells and interact with DNA. Our new DFMO CDs exhibit a robust advantage over conventional DFMO because they induce comparable reductions in viability at a dramatically lower concentration.

Ultimate goal of the nanomedicine is built on the idea of robust targeted delivery of complex assemblies that contain sufficient amount of multiple therapeutics and diagnostic agents for highly localized payload release with no adverse side effects. Besides the numerous efforts on the field of cancer specific nanomedicine, still there is a great need for improvements in terms of target specificity. Previously, we have reported a target-specific carbon dots- based dual nano-drug delivery system. In study, for the first time in literature, surface functional group of the carbon dots were conjugated with four different ligands namely, two peptides (shPep-1 and lnPep-1) and two chemotherapeutic drugs (epirubicin and temozolomide). Here, we advanced our drug delivery system as a dual drug nano-carrier (quadruple nano-model) that explicitly targets the IL-13Rα2 receptors and the nucleus of high-grade glioma brain tumors. The successful conjugation of each molecule onto carbon dots (CDs) was meticulously characterized with numerous analytical techniques. Additionally, the in vitro cell viability assay revealed that quadrupole nano-model significantly reduced the cancer cell viability compared to the single peptide dual drug linked conjugates. Further, in vitro bioimaging studies using FITC conjugated single and dual peptides models, showed that dual peptide model exhibited greater FITC fluorescence throughout the cell including the nucleus compared to the single peptide models. This observation is evidence for improved cancer cell uptake and nucleus colocalization of quadrupole nano-model. Our quadrupole nano-model fully serves the ultimate goal of nanomedicine as a nanocarrier which contains two targeting peptides and two therapeutics simultaneously.

Objective: Anterior cervical discectomy and fusion (ACDF) is the most common performed surgery in the cervical spine. Dysphagia is one of the most frequent complications following ACDF. Several studies have identified certain demographic and perioperative risk factors associated with increased dysphagia rates, but few have reported recent trends. Our study aims to report current trends and factors associated with the development of inpatient postoperative dysphagia after ACDF. Methods: The National Inpatient Sample was evaluated from 2004 to 2014 and discharges with International Classification of Diseases procedure codes indicating ACDF were selected. Time trend series plots were created for the yearly treatment trends for each fusion level by dysphagia outcome. Separate univariable followed by multivariable logistic regression analyses were performed to evaluate predictors of dysphagia. Results: A total of 1,212,475 ACDFs were identified in which 3.3% experienced postoperative dysphagia. A significant increase in annual dysphagia rates was observed from 2004-2014. Frailty, intraoperative neuromonitoring, 4 or more level fusions, African American race, fluid/electrolyte disorders, blood loss, and coagulopathy were all identified as significant independent risk factors for the development of postoperative dysphagia following ACDF. Conclusion: Postoperative dysphagia is a well-known postsurgical complication associated with ACDF. Our cohort showed a significant increase in the annual dysphagia rates independent of levels fused. We identified several risk factors associated with the development of postoperative dysphagia after ACDF.

Carbon dots (CDs) have been intensively studied since their discovery in 2004 because of their unique properties such as low toxicity, excellent biocompatibility, high photoluminescence (PL) and good water dispersibility. In this study metformin derived carbon dots (Met-CDs) were synthesized using a microwave assisted method. Met-CDs were meticulously characterized using ultra-violet spectroscopy (UV-vis), photoluminescence (PL), Fourier Transform Infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), atomic force (AFM) and transmission electron (TEM) microscopies. According to results of cytotoxicity studies, Met-CDs possess low-toxicity and excellent biocompatibility towards both non-tumor and tumor cell lines indicating that Met-CDs are outstanding candidates for living cell bioimaging studies. Furthermore, bioimaging studies have displayed that Met-CDs can penetrate the cell membrane and disperse throughout the cell structure including the nucleus and mitochondria. More specifically, Met-CDs tend to start localizing selectively inside the mitochondria of cancer cells, but not of non-tumor cells after 1 h of incubation. Finally, a zebrafish study confirmed that Met-CDs cross the blood-brain barrier (BBB) without the need of any other ligands. In summary, this study presents synthesis of Met-CDs which feature abilities such as mitochondrial and nucleus localizations along with BBB penetration. (c) 2021 Elsevier Inc. All rights reserved. Carbon dots (CDs) have been intensively studied since their discovery in 2004 because of their unique properties such as low toxicity, excellent biocompatibility, high photoluminescence (PL) and good water dispersibility. In this study metformin derived carbon dots (Met-CDs) were synthesized using a microwave assisted method. Met-CDs were meticulously characterized using ultra-violet spectroscopy (UV?vis), photoluminescence (PL), Fourier Transform Infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), atomic force (AFM) and transmission electron (TEM) microscopies. According to results of cytotoxicity studies, Met-CDs possess low-toxicity and excellent biocompatibility towards both non-tumor and tumor cell lines indicating that Met-CDs are outstanding candidates for living cell bioimaging studies. Furthermore, bioimaging studies have displayed that Met-CDs can penetrate the cell membrane and disperse throughout the cell structure including the nucleus and mitochondria. More specifically, Met-CDs tend to start localizing selectively inside the mitochondria of cancer cells, but not of non-tumor cells after 1 h of incubation. Finally, a zebrafish study confirmed that Met-CDs cross the blood?brain barrier (BBB) without the need of any other ligands. In summary, this study presents synthesis of Met-CDs which feature abilities such as mitochondrial and nucleus localizations along with BBB penetration.