Harnessing DNA Tetrahedral Nanoparticles: A Novel Strategy for Co- delivery of OTUD6B siRNA and DOX Against TNBC Growth and Progression

doi:10.21203/rs.3.rs-3416642/v1

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Harnessing DNA Tetrahedral Nanoparticles: A Novel Strategy for Co- delivery of OTUD6B siRNA and DOX Against TNBC Growth and Progression

https://doi.org/10.21203/rs.3.rs-3416642/v1

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Background

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking specific targeted therapeutic options. The deubiquitinizing enzyme OTUD6B is emerging as a potential player in TNBC progression.

Objective

The study aimed to ascertain the role of OTUD6B in TNBC progression and to exploit its therapeutic potential using a novel delivery system.

Methods

OTUD6B expression in TNBC was studied in relation to patient survival outcomes. We explored the potential of OTUD6B siRNA for TNBC treatment and its combined delivery with the chemotherapeutic agent, DOX, using a synthesized DNA tetrahedral nanoparticle (Td). The uptake and efficacy of the siOTUD6B/DOX@Td combination in TNBC cells were then evaluated, alongside an investigation into the underlying molecular mechanisms.

Results

There was a significant upregulation of OTUD6B in TNBC, inversely correlated with patient survival. The siOTUD6B/DOX@Td composite demonstrated efficient cellular uptake by TNBC cells, leading to the gene silencing of OTUD6B and controlled DOX release. This dual treatment approach enhanced apoptosis rates, increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis. In vivo results further confirmed the inhibition of tumor growth and metastasis without harming primary organs. Mechanistically, OTUD6B influenced TNBC progression through MDM2 stabilization and FOXO3 degradation.

Conclusion

Our findings highlight the pivotal role of OTUD6B in TNBC progression and underscore the potential of DNA tetrahedral nanoparticles as drug delivery systems. The combined siOTUD6B/DOX@Td strategy offers a promising therapeutic approach for TNBC and demonstrates the broader applicability of DNA nanotechnology in biomedicine.

Triple-negative breast cancer (TNBC)

OTUD6B

DNA tetrahedral nanoparticles

Breast carcinoma stands as the paramount malignant neoplasm afflicting the female population, marked by substantial morbidity and mortality indices[1].Triple-negative breast cancer (TNBC) emerges as a specialized sub-category of breast carcinoma, delineated by the conspicuous absence of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) expressions[2, 3]. This absence effectively renders TNBC impervious to conventional endocrine interventions and HER2-centric therapies[4]. Distinctive attributes of TNBC encompass augmented invasive propensities, recurrent episodes, metastatic tendencies, and attenuated survival probabilities, thereby erecting formidable impediments for clinical oversight[5]. Presently, chemotherapy perpetuates its reign as a primary therapeutic avenue for TNBC, with doxorubicin (DOX) frequently invoked as an expansive anti-neoplastic agent[6, 7]. Nevertheless, DOX administration carries with it inherent challenges, including dose-proportionate cardiotoxicity, the genesis of multidrug resistance, and indiscriminate systemic impacts[8–10]. In light of these considerations, an exigent imperative arises to delve into innovative therapeutic modalities that amplify DOX’s curative prowess while simultaneously tempering its detrimental sequelae.

In contemporary scientific discourse, an escalating body of evidence has underscored the cardinal function of the OTU family’s pivotal member, OTUD6B, in an array of pathologies[11–13]. Preliminary forays into the regulatory intricacies of OTUD6B, especially within neoplasms such as renal cell carcinoma, have delineated its propensity to foster neoplastic expansion and metastatic behaviors, notably through the stabilization of the mutant pVHL (von Hippel-Lindau tumor suppressor)[14–16]. Paradoxically, in certain malignancies like HCC, OTUD6B manifests as an inhibitory genetic entity[17]. Additionally, the nexus between OTUD6B-AS1 and paclitaxel resistance within triple-negative breast cancer has been discerned, with indications pointing towards its mediation of autophagy and genomic instability through the miR-26a-5p/MTDH axis[18]. Furthermore, knocking down the expression of OTUD7B may potentiate DOX-induced apoptosis[19]. Yet, the exact operational paradigm and mechanistic trajectory of OTUD6B within triple-negative breast cancer remain enigmatic.

To expound upon the potential influence and mechanistic schema of OTUD6B in triple-negative breast carcinoma (TNBC), we commenced by quantifying its expression within this cancer subset, subsequently discerning an association between OTUD6B expression, tumoral invasiveness, and pharmacological resistance. In our methodological approach, small interfering RNA (siRNA) technology was harnessed to effectuate the silencing of the OTUD6B gene, which culminated in the attenuation of TNBC cellular proliferation, invasive tendencies, and migratory capacities. Notably, when OTUD6B inhibition was conjoined with DOX therapeutic regimens, heightened DOX receptivity was observed. To address the complexities of siRNA delivery, we turned to the DNA tetrahedral framework. Comprising four autonomously-arranged single-stranded DNA moieties, these tetrahedral constructs are renowned for their stability[20], facile synthesis[21], programmability[22], and their profound implications in nuclear medical imaging[23], molecular diagnostics[24], and precision-driven delivery[25]. Our empirical endeavors successfully leveraged the DNA tetrahedral apparatus for the efficacious delivery of OTUD6B siRNA into TNBC cellular environments, engendering significant gene-silencing outcomes and observed potentiating effects in tandem with DOX administration. Subsequent mechanistic dissections unearthed that OTUD6B orchestrates TNBC cellular viability via the stabilization of MDM2 protein concentrations, succeeded by ubiquitin-facilitated degradation of the FOXO3 protein; this cascade may proffer insights into the mechanistic underpinnings that render OTUD6B an attractive therapeutic target. Collectively, our revelations promise to demystify the mechanisms undergirding TNBC pathogenesis and proffer innovative therapeutic avenues and clinical translational potential.

Enhanced OTUD6B Expression in Triple-Negative Breast Carcinoma (TNBC) Correlates Inversely with Patient Outcomes

To elucidate the expression magnitude and clinical ramifications of OTUD6B in triple-negative breast carcinoma (TNBC), an inaugural bioinformatics scrutiny was undertaken leveraging the breast carcinoma dataset from the TCGA repository. Utilizing the data analytics platform available at http://gepia.cancer-pku.cn/, we discerned a pronounced augmentation in the OTUD6B expression within TNBC neoplastic specimens when juxtaposed with their cognate peri-tumoral normal tissues, a trend observed pervasively across all breast carcinoma subcategories (Fig. 1A). Moreover, when TNBC neoplastic specimens were benchmarked against their respective paracancerous tissues, the OTUD6B expression levels were conspicuously amplified (Fig. 1B). The ensuing Kaplan-Meier survival trajectory analysis unveiled a correlation: elevated OTUD6B expression presaged diminished overall survival (OS) metrics in the TNBC cohort (Fig. 1C). This data nexus intimates a presumable instrumental role of OTUD6B in accentuating TNBC pathogenesis and modulating patient outcomes. To lend empirical weight to our bioinformatics revelations, we procured neoplastic and paracancerous specimens from TNBC-afflicted patients under our institutional care. Subsequent evaluations, employing immunohistochemical and Western blot methodologies, evinced markedly augmented OTUD6B protein concentrations within TNBC neoplastic specimens relative to their adjacent normative counterparts (Fig. 1D, E). This empirical data dovetails seamlessly with our bioinformatics inferences, reinforcing the proposition of heightened OTUD6B expression in TNBC and its correlation with a suboptimal prognosis.

siRNA-Mediated Knockdown of OTUD6B Attenuates Proliferative, Invasive, and Migratory Phenotypes of Triple-Negative Breast Carcinoma (TNBC) Cells and Augments Their DOX Receptivity

In our quest to decipher the functional implications of OTUD6B within the biological milieu of triple-negative breast carcinoma (TNBC) cells, we embarked on an analysis of its expression within TNBC cellular lines, specifically MDA-MB-231 and MDA-MB-453. EdU incorporation assays unambiguously illuminated the pronounced inhibitory impact of OTUD6B siRNA on the proliferative dynamics of TNBC cells (Fig. 2A-B). Complementarily, employing Transwell migration and scratch wound-healing assays, we ascertained that the OTUD6B siRNA engendered a substantive curtailment in the migratory and invasive capacities of TNBC cells (Fig. 2C-H). Collectively, this suite of observations postulates a facilitative role for OTUD6B in the proliferative, migratory, and invasive orchestrations of TNBC cells. Delving deeper into the nexus between OTUD6B and chemosensitivity in TNBC, we employed the CCK8 viability assay. Our findings elucidate that siRNA-mediated OTUD6B abrogation amplifies the cytotoxic response of TNBC cells to DOX, as manifested by a substantial diminution in their half maximal inhibitory concentration (IC50) vis-à-vis the control cohort (Fig. 2I-J).

Efficacious Incorporation of OTUD6B siRNA and DOX within an Engineered DNA Tetrahedral Framework

For the fabrication and conveyance of the OTUD6B siRNA and DOX using DNA tetrahedron nanoparticles, we harnessed a DNA self-assemblage technique. This methodology capitalizes on four singularly stranded DNAs (ssDNAs), founded on the axioms of nucleobase complementarity, to engineer a robust tetrahedral configuration (Td)^[22]. Of the quartet, three ssDNAs spanned 63 nucleotides (nt) in length, whilst the fourth extended to 87 nt. Following the engenderment of Td siOTUD6B via nucleobase complementarity, a concoction of DOX and siOTUD6B @ Td was forged, culminating in the resultant compound siOTUD6B/DOX @ Td, illustratively represented in Fig. 3A.

By meticulously refining synthesis parameters – encompassing temperature, chronological duration, ionic concentration, and auxiliary variables – we discerned the quintessential blueprint for crafting DNA tetrahedral nanoparticles. In particular, DNA tetrahedra were engineered under varying magnesium (Mg2+) ionic concentrations: 12.5 mM, 25 mM, and 50 mM. The derivatives from each synthetic phase were profiled via 8% polyacrylamide gel electrophoresis. Observations underscored that the electrophoretic band intensity, indicative of residual unreacted entities, was at its nadir, and synthetic yield peaked when Mg2 + concentrations oscillated between 12.5 mM and 25 mM (Fig. 3B). Balancing efficiency vis-à-vis economic considerations, a Mg2 + concentration of 12.5 mM was earmarked for ensuing synthetic endeavors. Atomic Force Microscopy (AFM) elucidations unveiled a distinctive tetrahedral morphology accompanied by homogeneous dimensions for the fabricated DNA tetrahedral nanoparticles (Fig. 3C). Such revelations authenticate the triumphant synthesis of our envisaged DNA tetrahedra.

Employing a UV spectrophotometric modality, we quantified the encapsulation prowess and the DOX assimilation rates. Data delineated a direct proportionality between drug assimilation and its increasing concentration, with a concomitant inverse relationship for encapsulation efficiency (Fig. 5D-E). These empirical outcomes fortify the successful integration of OTUD6B siRNA and DOX within DNA tetrahedral nanoparticles.

Efficient Intracellular Uptake of DNA Tetrahedra by TNBC Cells Facilitates Concurrent OTUD6B Gene Suppression and DOX Liberation

To ascertain the targeted proficiency of the DNA tetrahedral nanoparticles towards TNBC cells and the concomitant discharge of siOTUD6B and DOX for therapeutic intervention, TNBC cells were exposed to free siOTUD6B and siOTUD6B@Td. Laser confocal microscopy was subsequently deployed to monitor the intracellular assimilation of these nanoparticles. Observational data illuminated a pronounced augmentation in the fluorescence intensity within MDA-MB-231 and MDA-MB-453 cellular substrates post-treatment with siOTUD6B@Td vis-à-vis the isolated siRNA, underscoring the efficacious cellular endocytosis of siOTUD6B@Td complexes (Fig. 4a). A subsequent proteomic assessment via Western blotting unveiled a marked diminution in the OTUD6B protein abundance within the TNBC cells subjected to the siOTUD6B@Td regimen, in contrast to the control siRNA or the Td matrix incorporated with a scrambled siRNA. This ascertains the potent gene suppression effectuated by the siOTUD6B@Td amalgamation (Fig. 6b).

Pivoting towards the evaluation of DOX’s potentiating effects on TNBC post its integration within DNA tetrahedra, we orchestrated CCK8 experiments juxtaposing various nanoparticle concoctions. The empirical findings elucidated that cellular viability in MDA-MD-231 and MDA-MD-453 strains underwent significant curtailment upon therapeutic intervention using the siOTUD6/DOX@Td composite, as juxtaposed to solitary DOX@Td administration (Fig. 4D-E). Collectively, these revelations substantiate the premise that DNA tetrahedral nanoparticles adeptly permeate TNBC cells, orchestrating a dually therapeutic paradigm: silencing the OTUBD6 gene whilst concurrently liberating DOX, culminating in the amplified inhibition of TNBC cellular operations.

The Delivery via DNA Tetrahedral Vectors Markedly Attenuates Tumoral Proliferation in an In Vivo TNBC Cell Transplant Paradigm

To elucidate the in vivo antineoplastic potential of the DNA tetrahedral nanoparticles, we instituted a TNBC cell-transplanted tumorigenesis model as an experimental platform for drug conveyance assessment. Given the innate vulnerability of free siRNA to nuclease-mediated degradation in vivo, thereby compromising its therapeutic integrity, we juxtaposed the therapeutic outcomes among a Td vector-encapsulated scramble siRNA control cohort, the Td vector-incorporated siOTUD6B group, and the siOTUD6B/DOX@Td composite within the TNBC tumor framework. Upon culmination of the experimental period, tumoral evolution was chronicled, and associated tissues—both tumoral and organ-specific—were harvested for multifaceted analyses. The accrued tissues underwent procedural evaluations encompassing mass determination, photographic documentation, hematoxylin and eosin (HE) staining, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and proteomic profiling via Western blotting. Empirical observations underscored the pronounced anti-tumoral efficacy of the siOTUD6B/DOX@Td amalgamation, surpassing that of the scramble siRNA@Td and the isolated siOTUD6B@Td (Fig. 5A-B). This was further substantiated by a salient decrement in the tumoral mass (Fig. 5c). Histopathological examinations via HE staining unveiled that the siOTUD6B/DOX@Td composite potently diminished oncogenic cellular abundance whilst amplifying necrotic zones (Fig. 5D). Concurrently, TUNEL staining manifested a notable augmentation in apoptotic cellular prevalence upon administration of the siOTUD6B/DOX@Td composite (Fig. 5D). Proteomic analyses, as deduced from Western blotting, elucidated a tangible suppression in the OTUD6B protein abundance in tumors subjected to the siOTUD6B/DOX@Td regimen (Fig. 5E). Importantly, a thorough histopathological survey, via HE staining, failed to detect any discernible adverse effects on critical organ systems, including the spleen, pulmonary, and renal tissues (Fig. 5f). Cumulatively, these revelations bolster the premise that DNA tetrahedral vectors exhibit potent anti-tumoral capacities while preserving a commendable biosafety profile within in vivo TNBC transplantation constructs.

DNA Tetrahedral Vector Markedly Attenuates Metastatic Propagation in the TNBC-Derived Metastatic Paradigm

To authenticate the in vivo anti-metastatic potential of siOTUD6B/DOX@Td, we instituted a metastasis model predicated on TNBC cells, juxtaposing the therapeutic efficacy of the siOTUD6B/DOX@Td ensemble with scramble siRNA@Td and siOTUD6B@Td. Upon experimental culmination, murine lung tissue was procured, post-evaluating the respective survival trajectories. Histological analysis of the lung sections entailed both Bouin’s and hematoxylin and eosin (HE) staining. Empirical outcomes revealed that the siOTUD6B/DOX@Td composite manifested a profound suppression in the genesis of metastatic lung nodules, relative to both scramble siRNA@Td and siOTUD6B@Td (Fig. 6A-B). Additionally, an appreciable augmentation in overall survival was discernible among the treated cohorts (Fig. 6C). HE staining further illuminated a tangible decrement in oncogenic cellular abundance within the lung matrices subsequent to siOTUD6B/DOX@Td administration (Fig. 6D). Collectively, these insights accentuate the potency of our DNA tetrahedral vector in curbing metastatic spread within the TNBC-induced metastasis model.

OTUD6B is Implicated in TNBC Progression via MDM2 Stabilization and FOXO3 Protein Degradation

Seeking to delineate the molecular underpinnings associated with OTUD6B, we discerned its putative role as a suppressor of FOXO3. Exogenous augmentation of OTUD6B within MDA-MB-231 cells notably mitigated intracellular quotas of FOXO3 protein, whilst siRNA-mediated OTUD6B abrogation reciprocated with elevated FOXO3 expression (Fig. 7A). Given its deubiquitinating enzyme characterization, elevated OTUD6B was observed to amplify the ubiquitin-modification profile of FOXO3 (Fig. 7B). Ancillary literature has implicated OTUD6B-mediated regulation of the MDM2 ubiquitin ligase. Ergo, we ventured to probe the ramifications of OTUD6B on MDM2’s ubiquitination status and expression via immunoprecipitation assays (Fig. 7C). Empirical outputs from MDA-MB-231 cells corroborated an interactive alliance between OTUD6B and MDM2, modulating the latter’s ubiquitination dynamics (Fig. 7D). In both the overexpression and silencing paradigms pertaining to OTUD6B within MDA-MB-231 cellular systems, perturbations were observed at both transcriptional and translational echelons for OTUD6B, MDM2, and FOXO3 (Figs. 7E-G). Intriguingly, OTUD6B’s modulatory effect on FOXO3 appeared antithetical to its influence on MDM2 dynamics within MDA-MB-231 cells. These revelations underscore the potential of siRNA-mediated OTUD6B targeting to incapacitate TNBC cellular activities via curbing MDM2 deubiquitination and orchestrating the amplification of FOXO3 expression (Fig. 7H). Extending these molecular insights, cellular assays employing our synthesized siOTUD6B@Td nanoparticles corroborated that siOTUDB@Td treatment culminated in a marked abatement of OTUD6B expression while reciprocally elevating FOXO3 levels (Figures I-J), thus reinforcing the molecular mechanism wherein OTUD6B potentially stabilizes MDM2 entities and facilitates the catabolism of FOXO3 proteins, thereby modulating the trajectory of TNBC evolution.

This research undertakes a comprehensive exploration of the expression dynamics and consequential role of OTUD6B within the context of triple-negative breast cancer (TNBC). Furthermore, it delves into the prospective utility of siOTUD6B/DOX@Td as an avant-garde drug delivery medium tailored for TNBC therapeutics. Empirical data from our investigation unequivocally reveals a pronounced elevation in OTUD6B expression in TNBC, a trend that is disconcertingly associated with an adverse prognostic outcome, which consistent with previous research results[26]. On a functional plane, OTUD6B emerges as a stabilizer of MDM2 entities, an accelerator of FOXO3 protein catabolism, and a modulator of a gamut of TNBC cellular dynamics, encompassing growth, invasiveness, migratory propensity, tumorigenesis, and metastatic potential[27, 28]. Additionally, OTUD6B appears to undermine the vulnerability of TNBC cells to DOX—an established chemotherapeutic agent for this cancer subtype. However, DOX is encumbered by challenges, including suboptimal selectivity, heightened toxicity, and the formidable obstacle of multidrug resistance[29]. In an endeavor to surmount these therapeutic hurdles, we pioneered the design of self-orchestrating DNA tetrahedral nanoparticles (Td). This innovative vehicle is adept at concurrently transporting siOTUD6B and DOX to the desired cellular targets. Crucially, our empirical outcomes underscore the efficient cellular assimilation of siOTUD6B/DOX@Td assemblages by TNBC cells, culminating in the transcriptional repression of OTUD6B in tandem with a modulated DOX release profile. This orchestrated approach augments apoptotic indices within TNBC cellular matrices, amplifying their receptiveness to DOX-mediated therapeutic effects. This sensitization effect concomitantly attenuates cellular proliferation, invasive tendencies, and migratory behaviors, an observation corroborated across both in vitro and in vivo paradigms. Further bolstering the therapeutic promise of our approach, siOTUD6B/DOX@Td administration conspicuously inhibited both tumorigenic and metastatic propensities, with no discernible deleterious ramifications on pivotal organ systems. Collectively, these insights shed illuminating light on the multifaceted role of OTUD6B in TNBC and pave the way for the evolution of nuanced, precision-driven therapeutic interventions for this challenging breast cancer subtype.

In the current investigation, we empirically confirmed the pronounced expression of OTUD6B in the milieu of triple-negative breast cancer (TNBC). Its conspicuous expression in TNBC is inextricably linked with an adverse prognostic trajectory. This observation resonates with a precedent pan-cancer analysis that earmarked OTUD6B as a pivotal prognostic biomarker, hinting at its prospective significance in immunotherapeutic interventions[26]. In a deeper delve into the mechanistic role of OTUD6B, we discerned its regulatory influence on the ontogeny of TNBC cells and affiliated tumorigenic processes, facilitated predominantly through the stabilization of MDM2 molecules and catabolic actions on FOXO3 proteins. Interestingly, this modus operandi mirrors antecedent research, where OTUD6B steered the evolution of lung carcinoma cells and tumors via akin mechanisms, though with stabilization of MDM2 molecules and degradation of p53 proteins[30, 31]. It is worth noting that certain nuanced differences emerged, which can potentially be ascribed to tissue-specific modulations or intricate interactions with other molecular actors, culminating in varied outcomes. Furthermore, a pivotal insight from our findings indicates that OTUD6B silencing augments the vulnerability of TNBC cells to DOX, positioning OTUD6B as a salient factor interwoven with the web of chemotherapy resistance.

Our scholarly endeavor has laid the foundation by interrogating the expression dynamics and functional relevance of OTUD6B in TNBC, thereby cementing the theoretical underpinnings for its prospective utility as a novel therapeutic nexus. The genesis of our inquiry was predicated on the exploration of DNA tetrahedral nanoparticles, showcasing an avant-garde drug delivery paradigm in the realm of TNBC therapeutics. This journey unveiled transformative insights and methodologies, further bolstering the burgeoning domain of DNA nanotechnology in biomedicine. Marrying the transcriptional repression of OTUD6B with DOX-mediated chemotherapeutics, we unveiled a synergistic therapeutic paradigm, heralding a novel therapeutic strategy for targeted interventions in TNBC.

Nevertheless, our study is not without its limitations. The veracity of our findings remains anchored to a confined cohort of TNBC cell lines and in vivo models. Thus, future endeavors should espouse a more expansive spectrum to unearth the multifaceted molecular intricacies and associated signaling cogs associated with OTUD6B in TNBC. Additionally, our therapeutic focus remained tethered exclusively to DOX. Future research vistas should venture into diverse chemotherapeutic agents or amalgamate them with alternate therapeutic modalities, such as radiological interventions or immunotherapeutics, to amplify the therapeutic potential against TNBC.

In essence, the present investigation embarked on a meticulous examination of the expression dynamics and the quintessential biological roles embodied by OTUD6B within the framework of TNBC. Our insights unveiled OTUD6B’s instrumental role in catalyzing the progression of TNBC, thereby laying the foundational theoretical groundwork to postulate its potential as an avant-garde therapeutic nexus. A collateral objective of this study was to elucidate the prospective utility of DNA tetrahedral nanoparticles, positioning them as pioneering vectors in the domain of TNBC therapeutics. Our empirical findings underscored the propensity of these nanoparticles to be adeptly internalized by TNBC cells, culminating in the transcriptional repression of OTUD6B and ensuing release of DOX. Such orchestrated events manifest in the attenuation of TNBC cellular proliferation, invasive tendencies, migratory behavior, and a notable abatement of tumorigenic growth and metastatic cascades. Notably, our results extol the intrinsic biocompatibility and adaptive programmability of DNA tetrahedral nanoparticles, delineating their potential as precision-targeted therapeutic vehicles adeptly tailored to surmount the multifaceted challenges inherent to TNBC. This endeavor, thereby, pioneers novel conceptual paradigms and methodological frameworks for harnessing the transformative potential of DNA nanotechnology in contemporary biomedicine.

Acknowledgements

Not applicable.

Author contributions

WZ, XY and RG contributed to this work equally, WZ and YF designed experiments and wrote the manuscript, XY and JW conducted the vitro experiments and related analysis. XK, QL, YW and SZ synthesized and characterized the nanoparticles, RG and XY provided the clinical samples of BRCA patients, JW, JC and YF revised the manuscript, QL and YW performed statistical analysis of the data.

Funding

This work was supported by National Natural Science Foundation of China (82072940, 82173328). Beijing Municipal Science and Technology Project (No. Z211100002921006).

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

This study has been approved by ethical review by the ethics committee of Cancer Hospital Chinese Academy of Medical Sciences. The animal studies were approved by the Laboratory Animal Care and Use Committee of Cancer Hospital Chinese Academy of Medical Sciences.

Consent for publication

All the authors have reviewed and agreed for the publication of this manuscript.

Competing interests

The authors declare no conflict of interest.

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Harnessing DNA Tetrahedral Nanoparticles: A Novel Strategy for Co- delivery of OTUD6B siRNA and DOX Against TNBC Growth and Progression

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Results

Enhanced OTUD6B Expression in Triple-Negative Breast Carcinoma (TNBC) Correlates Inversely with Patient Outcomes

Efficacious Incorporation of OTUD6B siRNA and DOX within an Engineered DNA Tetrahedral Framework

DNA Tetrahedral Vector Markedly Attenuates Metastatic Propagation in the TNBC-Derived Metastatic Paradigm

OTUD6B is Implicated in TNBC Progression via MDM2 Stabilization and FOXO3 Protein Degradation

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1