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Deng, S.

Publications and source records attributed to Deng, S..

At least 37 records · Page 2Linked to original sources
bioRxiv2025

Androgen Deprivation-Induced TET2 Activation Fuels Prostate Cancer Progression via Epigenetic Priming and Slow-Cycling Cancer Cells

Advanced prostate cancer (PCa) frequently develops resistance to androgen deprivation therapy through various mechanisms including lineage plasticity. Slow-cycling cells (SCCs) have emerged as key players in adaptive responses to therapy, yet their role in PCa remains unclear. Through in silico analysis of single-cell RNA sequencing (scRNA-seq) data, we discovered that SCCs are enriched during pivotal stages of PCa progression, including the transition from androgen-dependent to castration-resistant states and the emergence of neuroendocrine PCa (NEPC). Using a tetracycline-inducible H2BeGFP reporter system, we confirmed SCC enrichment following androgen deprivation in both in vitro and in vivo models. Furthermore, we identified TET2 as a key regulator of SCCs, with its expression upregulated by androgen deprivation and positively correlated with SCC signature scores in PCa. Genome-wide 5-hydroxymethylcytosine (5hmC) profiling revealed increased hydroxymethylation after androgen deprivation, while TET2 knockdown reduced 5hmC levels at specific loci. Functional studies demonstrated that TET2 governs SCC maintenance, cell cycle progression, and DNA damage repair. Targeting TET2, either alone or in combination with an ATM inhibitor, significantly suppressed tumor growth, highlighting TET2 as a promising therapeutic target. Our study provides the first single-nucleotide resolution map of 5hmC dynamics in PCa, identifies a cell state driving epigenetic rewiring, and underscores the transformative potential of novel therapeutic strategies for advanced PCa.

cancer biology↗
bioRxiv2024

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult for the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA sequencing approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2 and NFKBIA that associated with mTOR pathway, inflammatory response and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, {gamma}-H2AX, {beta}-Gal and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of drug-resistant epilepsy patients with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent markers expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

neuroscience↗
bioRxiv2024

A genome-wide-level insight into HSF gene family of Rhodomyrtus tomentosa and the functional characterization of RtHSFA2s genes in thermal adaption

Heat shock transcription factor (HSF) is one of the most important regulatory elements in plant development and stress response. Rhohomyrtus tomentosa has many advantages in adapting to high temperature and humidity climates, whereas the inherence has barely been elucidated. In this study, we aimed to characterize the HSF family and investigate the thermal adaption mechanisms of R. tomentosa. We identified 25 HSF genes in the R. tomentosa genome. They could be classified into three classes: HSFA, HSFB, and HSFC. Gene duplication event is a major motivation for the expansion of the RtHSF gene family. Most of the genes in the same subclass share similar conserved motifs and gene structures. The cis-acting elements of the promoter regions of RtHSF genes are related to development, phytohormone signaling, and stress responses, and they vary among the genes even in the same subclass, resulting in different expression patterns. Especially, there exists subfunctionalization in the RtHSFA2 subfamily in responding to various abiotic stresses, viz. RtHSFA2a is sensitive to drought, salt, and cold stresses, whilst RtHSFA2b is mainly induced by heat stress. We further prove that RtHSFA2b might be of more importance in R. tomentosa thermotolerance, for Arabidopsis with overexpressed RtHSFA2b outperformed those with RtHSFA2a under heat stress, and RtHSFA2b has much higher transcription activity than RtHSFA2a in regulating certain heat shock response (HSR) genes. RtHSFA2a plays a role in transactivating RtHSFA2b. All these results provide a general prospect of the RtHSF gene family and enclose a basal thermal adaption mechanism of R. tomentosa.

plant biology↗
bioRxiv2024

Function of the alternative electron transport chain in the Cryptosporidium parvum mitosome

Cryptosporidium parvum and C. hominis possess a remanent mitochondrion called the mitosome, which lacks DNA, the tricarboxylic acid cycle, a conventional electron transport chain, and ATP synthesis. The mitosome retains ubiquinone and iron sulfur cluster biosynthesis pathways, both of which require protein import that relies on the membrane potential. It was previously proposed that the membrane potential is generated by electrons transferred through an alternative respiratory pathway coupled to a transhydrogenase (TH) that pumps hydrogens out of the mitosome. This pathway relies on an alternative oxidase (AOX) and type II NADH dehydrogenase (NDH2), which also exists in plants, some fungi, and several protozoan parasites. To examine this model, we determined the location and function of AOX and NDH2 in C. parvum. Surprisingly, we observed that NDH2 was localized to parasite surface membranes instead of the mitosome. Furthermore, a {Delta}ndh2 knockout (KO) strain was readily obtained, indicating that this protein is not essential for parasite growth. Although, AOX exhibited a mitosome-like staining pattern, we readily obtained an {Delta}aox knockout strain, indicating that AOX is also dispensable for parasite growth. The growth of the {Delta}aox strain was inhibited by the AOX inhibitors SHAM and 8-HQ to the same extent as wild type, indicating that AOX is not the target of these inhibitors in C. parvum. Collectively, our studies indicate that NDH2 and AOX are non-essential genes in C. parvum, necessitating an alternative mechanism for maintaining the mitosome membrane potential. ImportanceCryptosporidiosis is the leading cause of diarrhea in young children and immunocompromised individuals, particularly AIDS/HIV patients. The only FDA approved drug against cryptosporidiosis, nitazoxanide, has limited effectivity in immunocompromised patients and is not approved for usage in children under 1 year old. Genomic analysis and previous studies proposed an alternative respiration pathway involving alternative oxidase (AOX) and type II NAD(P)H dehydrogenase (NDH2), which are thought to generate the mitosome membrane potential in C. parvum. Additionally, AOX and NDH2 were nominated as potential drug targets, based on their absence in mammalian hosts and sensitivity of parasite growth to known inhibitors of AOX. However, our study demonstrated that NDH2 is not localized in mitosome, AOX non-essential for parasite growth, and knockout lines lacking this enzyme are equally sensitive to AOX inhibitors. These findings indicate that AOX and NDH2 are not ideal candidates for future drug development against cryptosporidiosis and force a re-evaluation for models of how the mitosome generate its membrane potential.

microbiology↗
bioRxiv2024

An antibiotic that mediates immune destruction of senescent cancer cells

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with pro-senescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a PANoptosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via JNK pathway activation. We show that a combination of a DR5 agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent NK and CD8+ T cell mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine IL18. SignificanceThe efficacy of multiple cancer drugs is limited by the induction of senescence, which enables cancer cells to evade cell death. We uncover here a new selective vulnerability of senescent cancer cells and we show that this vulnerability can be targeted with a commonly-used antibiotic. We show that a combination of senescence-inducing therapy, combined with this antibiotic causes a highly immunogenic cell death phenotype that further stimulates potent immune destruction of senescent cancer cells.

cancer biology↗
bioRxiv2024

GeneLLM: A Large cfRNA Language Model for Cancer Screening from Raw Reads

We present GeneLLM, a novel large language model that offers a transformative approach to non-invasive cancer detection and biomarker discovery by directly interpreting plasma cell-free RNA (cfRNA) sequences. Unlike traditional annotation-dependent methods, GeneLLM operates without prior knowledge, achieving significantly improved multi-cancer detection accuracy. Critically, GeneLLM identifies novel cfRNAs ( pseudo-biomarkers) originating from previously unannotated genomic regions-overlooked by existing methods-offering new therapeutic targets and insights into intercellular communication. This innovative, cost-effective approach bypasses traditional bioinformatics tools, generating novel pseudo-biomarkers that outperform existing methods even with low-depth sequencing data. Consequently, GeneLLM opens new avenues for biomarker discovery and expands our understanding of the extracellular transcriptomes role in cancer development.

bioinformatics↗
bioRxiv2024

An AINTEGUMENTA phospho-switch controls bilateral stem cell activity during secondary growth

Plant stem cells have the remarkable ability to give rise to distinct tissues and organs throughout development. Two concentric cylinders of actively dividing stem cells are the main drivers of radial thickening during secondary growth, each producing distinct vascular cell types towards the inside and the outside. While the molecular mechanisms underlying their initiation have been well studied, it remains unclear how these stem cell layers determine which cell type is generated. Here, we demonstrate that the cross-talk between the ERECTA (ER) receptor pathway and auxin signalling controls the amount and choice of output tissue in these two stem cell regions. Mechanistically, we show that the ER pathway phosphorylates the transcription factor AINTEGUMENTA, thereby modulating bilateral stem cell activity and favouring the differentiation of only one type of cell. Our results thus show that the phosphorylation status of ANT regulates root girth and biomass accumulation by influencing bilateral stem cell production. This highlights the critical role of post-translational modifications in plant growth and development. SignificanceThis study uncovers a critical regulatory mechanism governing bilateral stem cell activity during plant radial growth. Stem cells in the cambia proliferate and differentiate into specialized tissues like wood and cork, key sites of biomass accumulation. By exploring the interplay between the ERECTA (ER) receptor and auxin signalling, we reveal how these pathways modulate stem cell differentiation and radial thickening through the phosphorylation of the transcription factor AINTEGUMENTA (ANT). Phosphorylation status of ANT modulates stem cell activity, dictating the production of specific vascular cell types like wood thus controlling root girth. This research underscores the importance of post-translational modifications in plant development and provides a novel regulation underpinning stem cell differentiation, with significant implications for enhancing biomass accumulation as wood.

plant biology↗
bioRxiv2024

CRISPR-Cas9/Cas12a Systems for efficient genome editing and large genomic fragment deletions in Aspergillus niger

CRISPR technology has revolutionized fungal genetic engineering by accelerating the pace and expanding the feasible scope of experiments in this field. Among various CRISPR-Cas systems, Cas9 and Cas12a are widely used in genetic and metabolic engineering. In filamentous fungi, both Cas9 and Cas12a have been utilized as CRISPR nucleases. In this work we first compared efficacies and types of genetic edits for CRISPR-Cas9 and -Cas12a systems at the polyketide synthase (albA) gene locus in Aspergillus niger. By employing a tRNA-based gRNA polycistronic cassette, both Cas9 and Cas12a have demonstrated remarkable editing efficacy. Cas12a demonstrated superiority over Cas9 protein when one gRNA was used for targeting, achieving an editing efficiency of 89.5% compared to 15% for Cas9. Moreover, when employing two gRNAs for targeting, both systems achieved up to 100% editing efficiency for single gene editing. In addition, the CRISPR-Cas9 system has been reported to induce large genomic deletions in various species. However, its use for engineering large chromosomal segments deletions in filamentous fungi still requires optimization. Here, we engineered Cas9 and - Cas12a-induced large genomic fragment deletions by targeting various genomic regions of A. niger ranging from 3.5 kb to 40 kb. Our findings demonstrate that targeted engineering of large chromosomal segments can be achieved, with deletions of up to 66.7% efficiency. Furthermore, by targeting a secondary metabolite gene cluster, we show that fragments over 100 kb can be efficiently and specifically deleted using the CRISPR-Cas9 or -Cas12a system. Overall, in this paper, we present an efficient multi-gRNA genome editing system utilizing Cas9 or Cas12a that enables highly efficient targeted editing of genes and large chromosomal regions in A. niger.

microbiology↗
bioRxiv2024

Unveiling the mechanisms of black phosphorus nanosheets-induced viable but non-culturable state in Bacillus tropicus

The release of black phosphorus (BP) nanosheets has raised concerns regarding potential ecological risks. Previous studies have confirmed their toxicity to bacteria, but discrepancies were observed between results obtained from the growth curve and colony forming unit (CFU) methods, indicating the possibility of bacterial cells entering a viable but non-culturable (VBNC) state induced by BP nanosheets. To accurately assess the risks, it is crucial to understand the underlying mechanisms. In this study, we investigated the effect of BP nanosheets on Bacillus tropicus, a gram-positive bacterium, using transcriptome sequencing and biological assays. Our findings revealed that BP nanosheets caused minimal cell death but predominately induced the VBNC state in most cells. At the transcriptional level, we observed significant down-regulation of pathways associated with cellular metabolism and respiratory chain in response to BP nanosheet treatment. Bacterial cells in the VBNC state exhibited depressed respiration to maintain basal cellular activity. Additionally, the reduced cellular respiration and metabolic activity were associated with a decrease in antibiotic susceptibility of the bacteria. These results provide new insights into the antibacterial mechanisms of BP nanosheets and emphasize the necessity of employing appropriate approaches, beyond the traditional CFU method, to assess the bacterial toxicity of nanomaterials. Environmental implicationBacteria play a crucial role as indicators in ecological risk assessment. Although numerous studies have highlighted the exceptional antibacterial properties of black phosphorus (BP) nanosheets, the unique viable but non-culturable (VBNC) state of bacteria is often overlooked when evaluating the ecological risks of nanomaterial, including BP nanosheets. In our study, we found that BP nanosheets can induce Bacillus tropicus into a VBNC state by suppressing cellular metabolism- and respiratory chain-related pathways, shedding light on their ecological risk assessment implications. This finding underscores the importance of utilizing appropriate approaches in evaluating the bacterial toxicity of nanomaterials.

pharmacology and toxicology↗
bioRxiv2024

Biological activity of a stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor, 60c, in metastatic, triple-negative breast cancer

BackgroundImproving survival for patients diagnosed with metastatic disease and overcoming chemoresistance remain significant clinical challenges in treating breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of therapeutically targetable receptors (ER/PR/HER2). TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel will develop taxane resistance (TxR). We previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), VERU-111, inhibits TNBC tumor growth and treats pre-established metastatic disease. To further improve the potency and metabolic stability of VERU-111, we created next-generation derivatives of its scaffold, including 60c. Results60c shows improved in vitro potency compared to VERU-111 for taxane-sensitive and TxR TNBC models, and suppress TxR primary tumor growth without gross toxicity. 60c also suppressed the expansion of axillary lymph node metastases existing prior to treatment. Comparative analysis of excised organs for metastasis between 60c and VERU-111 suggested that 60c has unique anti-metastatic tropism. 60c completely suppressed metastases to the spleen and was more potent to reduce metastatic burden in the leg bones and kidney. In contrast, VERU-111 preferentially inhibited liver metastases and lung metastasis repression was similar. Together, these results position 60c as an additional promising CBSI for TNBC therapy, particularly for patients with TxR disease.

cancer biology↗
bioRxiv2024

TMEM63B functions as a mammalian thirst receptor

Thirst drives animals to reinstate water homeostasis by fluid intake. An increase of blood osmolality is thought to induce thirst by activating a thirst receptor expressed in the subfornical organ (SFO), but the molecular identity of this receptor remains elusive. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian thirst receptor in the SFO and mediates osmotic and dehydrated thirst. First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation. Heterologously expressed TMEM63B is activated by hypertonic stimuli and point mutations can alter the reversal potential of the channel. More importantly, purified TMEM63B in liposomes establishes osmolarity-gated currents. Finally, Tmem63b knockout mice have profound deficits in thirst, and deleting TMEM63B within the SFO neurons recapitulated this phenotype. Taken together, these results provide a molecular basis for thirst 82and demonstrate TMEM63B is the long-sought mammalian thirst receptor.

neuroscience↗
bioRxiv2024

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Genetic variation in the regulation of gene expression contributes substantially to phenotypic variation. Understanding how variation in DNA sequences and epigentic modifications leads to gene expression variation remains a challenging task. In hybrid animals where cellular environments are homogeneous, differences between the expression of paternal and maternal alleles must be due to cis sequence or epigenic differences. Therefore, hybrid mapping is a powerful approach to efficiently identify and characterize genes under regulation through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we performed a comprehensive multi-omic characterization of regulatory variation across brain, liver, muscle, and placenta in four developmental stages. We produced one of the largest multi-omic datasets to date in pigs, including 16 whole genome sequenced genomes, 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We developed a novel read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We showed that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identified 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. By integrating methylation, chromatin accessibility, and gene expression data, many of these allele specific expression can be explained by allele specific methylation and/or chromatin accessibility. This study provides one of the most comprehensive characterizations of regulatory variation across multiple tissues and developmental stages in pigs and offers new opportunity of genetic improvement for this important food animal species.

developmental biology↗
bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗
bioRxiv2023

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Statement of SignificanceThis study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2s oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

cancer biology↗
bioRxiv2023

Microglia facilitate and stabilize the response to general anesthesia

General anesthesia leads to a loss of consciousness and an unarousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.

neuroscience↗
bioRxiv2023

Ultrasound-Induced Reorientation for Multi-Angle Optical Coherence Tomography

Organoid and spheroid technology have recently provided great insights into oncology, developmental biology as well as personalized medicine. Among the methods to optically monitor the structural and functional organization of such samples, optical coherence tomography (OCT) has emerged as an excellent, label-free approach. Mature organoids, however, are often too opaque for OCT due to regions of strong attenuation. This leads to severe artifacts and reduced morphological tissue information in the reconstruction, since the far-side of the specimen is not reachable. Access to multi-angle views of OCT is therefore highly desirable. This aligns with another problem affecting certain goals of organoid research: The sample needs to be embedded in a growth scaffold such as Matrigel, whereas freely floating objects would not suffer from confinement and be more easily accessible for mechanical or chemical probing. Here we present ULTrasound-Induced reorientation for Multi-Angle-OCT (ULTIMA-OCT), a solution overcoming these limitations. By inserting a small 3D-printed acoustic trap to a spectral-domain OCT system, acoustic actuation enables contact-free levitation and finely tunable stepwise reorientation of samples such as zebrafish larvae and tumor spheroids, in a controlled and reproducible manner. This enables tomographic reconstruction of (sub-)mm samples with enhanced penetration depth and reduced attenuation artifacts, by means of a model-based algorithm we developed. We show that this approach is able to fuse the diverse multi-angle OCT volumes for a joint recovery of 3D-reconstruction of reflectivity, attenuation, refractive index and position registration for zebrafish larvae. We believe that our approach represents a powerful enabling tool for developmental biology and organoid research.

bioengineering↗
bioRxiv2023

Logic Gate Activated Lysosome Targeting DNA Nanodevice for Controlled Proteins Degradation

Targeted protein degradation (TPD) is a powerful technique for regulation of protein homeostasis. Current TPD mainly focuses on the therapeutical consequences rather than the operation processes of the molecular tools. Herein, we construct a platform for precisely manipulate the protein degradation by activatable lysosome targeting DNA nanodevices. In the design, a lysosome-targeting CD63 aptamer is locked by the single-stranded DNA with a photocleavable group and a disulfide bond. This locked CD63 aptamer is connected with the aptamer targeting the protein of interest via double-stranded DNA linkages to form the logic-gate activated lysosome targeting DNA nanodevice (LALTD). With the UV light and endogenous GSH as inputs, AND logic-gate is built to efficiently manipulate the protein delivery processes by LALTD. The protein of interest could be degraded via efficient lysosome hydrolysis. Further studies shows that the logic-gate operation could be used for modulating the T cell-mediated antitumor immunity. The modularly designed activatable lysosome targeting DNA nanodevices exhibits good stability, controllability, programmability and universality, providing a new prospect for accurate protein degradation and precise therapy. Entry for the Table of ContentsThrough rational integration of dual molecular switches with bispecific aptamer systems, a logic-gate activated lysosome targeting DNA nanodevice (LALTD) was developed for precisely controlled process of protein hydrolysis in living cells. The designed LALTD system provide a general platform for designing accurate protein degradation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/555427v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@1b3afc1org.highwire.dtl.DTLVardef@1d7c893org.highwire.dtl.DTLVardef@1b14268org.highwire.dtl.DTLVardef@7ed354_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗