DNA Structure Research Articles

Synergistic Regulation of DNA Morphology by Metal Cations and Low pH.

As a flexible biomolecule, the spatial structure of DNA is variable. The effects of concentration, metal cations, and low pH on DNA morphology were studied. For the high concentration of DNA, the cross-linked branch-like or network structures were formed. For the low concentration of DNA, isolated, random and freely loose linear DNA chains were presented. These phenomena were related to the intermolecular interactions. Branch-like DNA structures were reformed with the addition of metal cations to the low concentration of DNA at pH 7-4, suggesting the negative charges of DNA were neutralized, thus transforming the spatial structure of DNA into a low charge density morphology and presenting the hypochromic effect. Compared to the monovalent alkaline metal cations, more negative charges of DNA were screened by the alkaline-earth metal cations. Distinct DNA morphologies were observed for pH 3. The linear and condensed DNA structures were simultaneously observed, which was met regardless of the solution with or without the addition of metal cations. This was further confirmed by the absorbance of DNA. Compared to the pure DNA, bulky and aggregated DNA collapsed structures were formed when the sodium and magnesium cations were added to the reaction solution. In addition, it was verified that the condensed DNA structures failed to revert back to the chain structure by neutralizing acidic solutions with alkali, but the compacted DNA spheres became loose. The conductivities of various DNA morphologies were measured. They were morphology-dependent. This study provides guidance forthe behavior of DNA in the acidic solutions and further promotes the application of DNA in DNA-based nano-optoelectronic devices.

Abstract PR020: A novel framework for epigenome-dependent multimodal fragment-signature analysis reveals insights into cell-free DNA generation in cancer

Abstract Background: The genome-wide pattern of cell-free DNA (cfDNA) is influenced by fragmentation enzymes, nucleosome occupancy, and epigenetic factors, as well as cell death mechanisms. Better modeling of these factors and their interactions will be essential for more sensitive detection of tumor-specific features and tissue-of-origin. Methods: To obtain mechanistic insights into cfDNA fragmentation, we developed a fragmentomics signature analysis framework. Our fragmenTopics algorithm (i) decomposes contributions of different fragment lengths and end-motif signatures using topic modeling and (ii) learns the dependencies of signature rates on the epigenome. The second component utilizes gradient boosting, enabling the modeling of non-linear dependencies and feature interactions. Both large-scale features, such as histone marks and DNase activity, and meso-scale features, such as transcription start sites (TSSs), nucleosome positions, and secondary DNA structures, are included in the model. Results: Using de novo signature discovery from 726 samples across five datasets, we built a comprehensive catalog of fragment length and end-motif signatures and studied determinants of their activity across the genome. The most common length and end-motif signatures reflected the mononucleosomal fragmentation by DNASE1L3. These signatures, as well as the dinucleotide length signature and motif signatures associated with known motifs of DNase enzymes, such as DFFB, showed lower abundance in cancer and further decreased with increasing tumor fraction. Instead, cancer samples manifested a higher diversity of processes, many of which are of unknown origin. Notably, two cancer-enriched length signatures were, on average, 20 bp shorter fragments with respect to mono- and di-nucleosome peaks. These signatures correlated with H3K4me1 and the compartment eigenvector, and may be linked to tighter nucleosome wrapping in euchromatin. Two cancer-enriched signatures (190-240 bp and 240-300 bp) had higher rates in TSSs; in addition to the two tight mono- and di-nucleosomal signatures, which were also enriched. Cancer-enriched end-motifs were A/T-rich, and these did not correspond to known DNase motifs. The increased diversity in end-motifs may be due to non-apoptotic cell death or tissue- or cancer-specific activity of less-studied cleavage enzymes; our results on their epigenome correlations can inform further investigations into their etiology. Conclusion: Our signature-based fragmentomics framework, which decouples the contributions of distinct processes while identifying the epigenomic determinants of their genome-wide rates, can improve our understanding of cell-free DNA fragmentation in cancer. Citation Format: Yoo-Na Kim, Sangmi Lee, Allen Lynch, Tae Hee Kim, Peter J Park, Doga Gulhan. A novel framework for epigenome-dependent multimodal fragment-signature analysis reveals insights into cell-free DNA generation in cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR020.

Advancing Topoisomerase Research Using DNA Nanotechnology.

In this Perspective, the use of DNA nanotechnology is explored as a powerful tool for studying a family of enzymes known as topoisomerases. These enzymes regulate DNA topology within a living cell and play a major role in the pharmaceutical field, serving as anti-cancer and anti-bacterial targets. This Perspective will provide a short historical overview of the methods employed in studying these enzymes and emphasizing recent advancements in assays using DNA nanotechnology. These innovations have substantially improved accuracy and expanded the understanding of enzyme activity. This perspective will showcase the versatile utility of DNA nanotechnology in advancing scientific knowledge and its application in exploring new drug candidates, particularly in the study of topoisomerase enzymes.

Tandem-Controlled Dynamic DNA Assembly Enables Temporally-Selective Orthogonal Regulation of cGAS-STING Stimulation.

Despite advances in the controlled reconfiguration of DNA structures for biological applications, the dearth of strategies that allow for orthogonal regulation of immune pathways remains a challenge. Here, we report for the first time an endogenous and exogenous tandem-regulated DNA assembly strategy that enables orthogonally controlled stimulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. A DNA motif containing two palindromic sequences is engineered with an abasic site (AP)-connected blocking sequence to inhibit its self-assembly function, while apurinic/apyrimidinic endonuclease 1 (APE1)-triggered enzymatic cleavage of the AP site enables the reconfiguration and self-assembly of DNA motif into long double-stranded structures, thus realizing allosteric activation of the catalytic activity of cGAS to produce 2'3'-cyclic-GMP-AMP for STING stimulation. Importantly, we demonstrate that APE1-regulated DNA assembly allows for cell-selective activation of cGAS-STING signaling. Furthermore, by re-engineering the DNA motif with a photocleavable group, enzyme-triggered DNA assembly allows the cGAS-STING stimulation to operate (switched "ON''), whereas light-mediated fragmentation of the double-stranded DNA enables termination of such stimulation (switched "OFF"), thereby achieving orthogonal control over immune regulation. This work highlights an endogenous and exogenous tandem regulated strategy to modulate the cGAS-STING pathway in an orthogonally controlled manner.

Tandem‐Controlled Dynamic DNA Assembly Enables Temporally‐Selective Orthogonal Regulation of cGAS–STING Stimulation

Despite advances in the controlled reconfiguration of DNA structures for biological applications, the dearth of strategies that allow for orthogonal regulation of immune pathways remains a challenge. Here, we report for the first time an endogenous and exogenous tandem‐regulated DNA assembly strategy that enables orthogonally controlled stimulation of the cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. A DNA motif containing two palindromic sequences is engineered with an abasic site (AP)‐connected blocking sequence to inhibit its self‐assembly function, while apurinic/apyrimidinic endonuclease 1 (APE1)‐triggered enzymatic cleavage of the AP site enables the reconfiguration and self‐assembly of DNA motif into long double‐stranded structures, thus realizing allosteric activation of the catalytic activity of cGAS to produce 2’3’‐cyclic‐GMP‐AMP for STING stimulation. Importantly, we demonstrate that APE1‐regulated DNA assembly allows for cell‐selective activation of cGAS–STING signaling. Furthermore, by re‐engineering the DNA motif with a photocleavable group, enzyme‐triggered DNA assembly allows the cGAS–STING stimulation to operate (switched "ON''), whereas light‐mediated fragmentation of the double‐stranded DNA enables termination of such stimulation (switched "OFF"), thereby achieving orthogonal control over immune regulation. This work highlights an endogenous and exogenous tandem regulated strategy to modulate the cGAS–STING pathway in an orthogonally controlled manner.

Nonlinear mechanical response of finite-length soft composites with random dislocations

The effects of random dislocations on the vibrational properties of finite-length RNA and DNA macro-structures have been investigated by means of a harmonic Hamiltonian and the Green’s function method. The RNA molecule has been modeled using a half ladder model, and three models (a fishbone model and two different strand models) have been employed to model the structure of DNA. The lengths of the finite and cyclic systems are gradually increased to more accurately approximate the structures of RNA and DNA. Springs whose behaviors are governed by Hooke’s constitutive law have been used to represent the bonds between the masses, with the stiffness of the vertical springs randomly changing along the length of each model. This results in a more realistic representation of the inherent randomness of the studied structures. To investigate the effect of random dislocations on the mechanical response of the studied systems, it has been assumed that a random mass-spring ensemble has been knocked out of place by an external force. It has been found that increasing the number of building blocks along the length of the models suppresses the influence of dislocations on the vibration spectra of RNA and DNA. It was also observed that at low frequencies, the influence of dislocations becomes more pronounced. Besides, taking into account the collective mass of the sugar-phosphate backbone results in the appearance of gaps in the vibration spectra. By introducing dislocations into the models, additional dislocation-induced vibrational states appear in the DOS curves. What stands out from the results is that the responses of the studied systems to these changes are strictly nonlinear. The employed methodology can be applied to investigate the mechanical response of damaged RNA and DNA.

Untangling bacterial DNA topoisomerases functions.

Topoisomerases are the main enzymes capable of resolving the topological constraints imposed by DNA transactions such as transcription or replication. All bacteria possess topoisomerases of different types. Although bacteria with circular replicons should encounter similar DNA topology issues, the distribution of topoisomerases varies from one bacterium to another, suggesting polymorphic functioning. Recently, several proteins restricting, enhancing or modifying the activity of topoisomerases were discovered, opening the way to a new area of understanding DNA topology management during the bacterial cell cycle. In this review, we discuss the distribution of topoisomerases across the bacterial phylum and current knowledge on the interplay among the different topoisomerases to maintain topological homeostasis.

Distribution of Recessive Genetic Defect Carriers in Holstein Friesian Cattle: A Polish Perspective

Genetic disorders are caused by a hereditary change in the structure of DNA that may hurt the health and life of animals. Several recessive haplotypes and a few causative mutations are known in Holstein Friesian cattle: CDH (Holstein cholesterol deficiency), haplotypes with a homozygous deficiency in Holstein (HH1, HH3, HH4, HH5, HH6, HH7), BLAD (bovine leukocyte adhesion deficiency), DUMPS (deficiency of uridine monophosphate synthase), FXI (factor XI deficiency), HHM (mule foot, syndactyly), and BC (citrullinaemia). From a breeding point of view, these genetic diseases have highly negative effects and are a significant problem for breeders, exposing them to economic losses and hurting animal welfare. This study aimed to characterize the Polish population of Holstein Friesian dairy cattle, considering the carrier status of twelve selected genetic defects. This study was based on genotype data collected from 78,884 cows and 691 bulls of the Holstein Friesian variety. The studies were performed using Illumina Infinium microarrays. Among both bulls and cows, the highest numbers of carriers were detected for HH5 (appropriately 6.7% and 5.4%). The lowest numbers of carriers were detected for DUMPS, factor XI, and HHM. The study revealed one calf suffering from cholesterol deficiency.

A Rationally Designed Azobenzene Photoswitch for DNA G‐Quadruplex Regulation in Live Cells

AbstractG‐quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4‐specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light‐responsive G4‐binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4‐associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain, Q‐Azo4F‐C, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its trans and cis configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25‐fold reversible cytotoxic activity. Immunostaining conducted with the structure‐specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo‐driven reversible regulation of G4 structures in lung cancer cells by Q‐Azo4F‐C. Our findings highlight the potential of light‐responsive G4‐binders in advancing precision cancer therapy through dynamic control of G4‐mediated pathways.

Close Proximity of Cholesterol Anchors in Membrane Induces the Dissociation of Amphiphilic DNA Strand from Membrane Surface.

Dynamic DNA nanotechnology is appealing for membrane surface engineering due to their versatility and programmability. To modulate the dynamic interactions between the DNA functional units immobilized on membrane surface, membrane-anchored DNA functional units often come into close proximity each other due to DNA base pairing, which also leads to the close contact of the hydrophobic anchors in membrane. However, whether the close contact of hydrophobic anchors induces the dissociation of amphiphilic DNA structures from membrane surface is not concerned. Herein, we utilized cholesterol-labeled single-stranded DNA (ssDNA) as a simplified amphiphilic DNA structure to investigate the stability of membrane anchored DNA strands upon the closely contact of cholesterol anchors. The close contact of cholesterol-labeled ssDNA molecules driven by toe-hold mediated strand displacement reaction leads to approximately 41 % membrane anchored ssDNA dissociation from membrane surface, indicating the proximal cholesterol anchors in membrane could reduce the anchoring stability of cholesterol-modified DNA strands. This work enhances our understanding of the interactions between amphiphilic DNA and membranes, and provides valuable insights for the design of future DNA constructs intended for applications involving dynamic DNA reactions on membrane surface.

In-situ cation-exchange deposited Ag2S/In4SnS8 of Z-type heterojunction coupled with DNA recycling amplification for photoelectrochemical biosensing

Herein, a novel photoelectrochemical (PEC) biosensor was developed utilizing an in situ cation-exchange method to deposit a high-performance Ag2S/In4SnS8, a Z-type heterojunction with co-shared S atoms, as a signal indicator and using DNA recycling amplification for the sensitive and accurate detection of miRNA-141. The photosensitive Ag2S deposited on the In4SnS8 surface not only facilitated the rapid generation of photoelectrons but also formed a Z-type heterojunction with In4SnS8, effectively inhibiting electron-hole pair recombination. This resulted in a considerable improvement in the photoelectric conversion efficiency of Ag2S/In4SnS8, yielding an ∼ 120-fold increase in photocurrent compared to that of In4SnS8 under 660-nm visible-light irradiation. Furthermore, the arborescent DNA structure formed by hybrid chain reaction (HCR) enhanced the steric effect, thereby reducing the PEC response. Importantly, numerous quenchers MnPP competed for light absorption and captured photogenerated electrons in the valence bands of In4SnS8 and Ag2S, reducing electron transfer to the electrode and further considerably reducing the photocurrent. This enabled the sensitive detection of miRNA-141 across a concentration range from 10 amol·L−1 to 100 pmol·L−1, with a limit of detection as low as 3.3 amol·L−1 (S/N = 3). The proposed biosensor exhibits excellent stability and is expected to be applied for detecting clinically relevant disease markers.

Measurement of circular intensity differential scattering (CIDS) from single optically trapped biological particles

The circular intensity differential scattering (CIDS), which is the normalized Mueller matrix element -S14/S11, has been measured from single biological particles as a function of scattering angle. CIDS is valuable for its potential in detecting chiral particles that may include the helical structures of DNA or RNA molecules in biological samples, and as such is a potential method for detecting biological particles. Optical trapping is employed to levitate single particles within a custom-designed elliptical reflector for CIDS measurements. The advantage of optical levitation in light-scattering measurements is that single particles can be suspended in air with sufficient working distance to prevent interference from the suspending apparatus. To measure the phase function, the reflector is used to collect the angle-dependent scattering signals. We demonstrated that we can obtain two-dimensional angular optical scattering (TAOS) patterns that cover a wide angular range from single levitated particles. These TAOS patterns are generated using 532 nm illumination of left-handed and right-handed circular polarizations and recorded from trapped single particles (silica, English Oak, Ragweed, Mulberry, Glycine, and l-Aspartic acid).

A General DNA-Like Hybrid Symbiosis Framework: An EEG Cognitive Recognition Method.

In electroencephalogram (EEG) cognitive recognition research, the combined use of artificial neural networks (ANNs) and spiking neural networks (SNNs) plays an important role to realize different categories of recognition tasks. However, most of the existing studies focus on the unidirectional interaction between an ANN and a SNN, which may be overly dependent on the performance of ANNs or SNNs. Inspired by the symbiosis phenomenon in nature, in this study, we propose a general DNA-like Hybrid Symbiosis (DNA-HS) framework, which enables mutual learning between the ANN and the SNN generated by this ANN through parametric genetic algorithm and bidirectional interaction mechanism to enhance the optimization ability of the model parameters, resulting in a significant improvement of the performance of the DNA-HS framework in all aspects. By comparing with seven typical EEG cognitive recognition models, the performance of the seven hybrid network frameworks constructed using this method on different EEG-based cognitive recognition tasks are all improved to different degrees, verifying the effectiveness of the proposed method. This unified hybrid network framework similar to the DNA structure is expected to open up a new approach and form a new research paradigm for EEG-based cognitive recognition task.

Contribution of DNA/RNA Structures Formed by Expanded CGG/CCG Repeats Within the FMR1 Locus in the Pathogenesis of Fragile X-Associated Disorders.

Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds.

Computational study of the HLTF ATPase remodeling domain suggests its activity on dsDNA and implications in damage tolerance

The Helicase-Like Transcription Factor (HLTF) is member of the SWI/SNF-family of ATP dependent chromatin remodellers known primarily for maintaining genome stability. Biochemical and cellular assays support its multiple roles in DNA Damage Tolerance. However, the lack of sufficient structural data limits the comprehension of the molecular basis of its modes of action.In this work we have modelled and characterized the HLTF ATPase remodeling domain by using bioinformatic tools and all-atoms molecular dynamics simulations.In-silico results suggested that its binding to dsDNA is mainly mediated by the positively charged residues Arg563 and Lys913, found conserved in HLTF homologs, and Arg620 and Lys999, found only in HLTF. Interestingly, these residues are mutated in cancer cells. During translocation on dsDNA, HLTF remains persistently bound through the N-terminal ATPase subunit. However, DNA advancement occurs only in the presence of the synergic-anticorrelated action of both motor lobes. In contrast, the C-terminal facilitates substrate remodeling through DNA deformation and generation of bulges according to a wave-model. Finally, the large conformational change suggested between the two motor-remodeling subunits might be activated upon the release of PARP1 on stalled fork and be responsible for the intervention of HLTF-HIRAN in the formation of D-loop and 4-way junction DNA structures.

Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection.

Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.

How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites.

One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. Staphylococcus aureus (S. aureus) DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria. Crystal structures of uncleaved DNA with a gepotidacin precursor (2.1 Å GSK2999423) or with doubly cleaved DNA and zoliflodacin (or with its progenitor QPT-1) have been solved in the same P61 space-group (a = b ≈ 93 Å, c ≈ 412 Å). This suggests that it may be possible to observe the two DNA cleavage steps (and two DNA-religation steps) in this P61 space-group. Here, a 2.58 Å anomalous manganese dataset in this crystal form is solved, and four previous crystal structures (1.98 Å, 2.1 Å, 2.5 Å and 2.65 Å) in this crystal form are re-refined to clarify crystal contacts. The structures clearly suggest a single moving metal mechanism-presented in an accompanying (second) paper. A previously published 2.98 Å structure of a yeast topoisomerase II, which has static disorder around a crystallographic twofold axis, was published as containing two metals at one active site. Re-refined coordinates of this 2.98 Å yeast structure are consistent with other type IIA topoisomerase structures in only having one metal ion at each of the two different active sites.

A Highly Tumor-Permeating DNA Nanoplatform for Efficient Remodeling of Immunosuppressive Tumor Microenvironments.

The immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure-based nanoplatform with striking tumor-penetrating capability for targeted remodeling of the immunosuppressive tumor microenvironment in vivo. In our design, chemo-immunomodulator (gemcitabine) can be precisely grafted on DNA sequences through a reactive oxygen species (ROS)-sensitive linker. After self-assembly, the gemcitabine-grafted DNA structure can site-specifically organize legumain-activatable melittin pro-peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi-type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.

A Highly Tumor‐Permeating DNA Nanoplatform for Efficient Remodeling of Immunosuppressive Tumor Microenvironments

AbstractThe immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure‐based nanoplatform with striking tumor‐penetrating capability for targeted remodeling of the immunosuppressive tumor microenvironment in vivo. In our design, chemo‐immunomodulator (gemcitabine) can be precisely grafted on DNA sequences through a reactive oxygen species (ROS)‐sensitive linker. After self‐assembly, the gemcitabine‐grafted DNA structure can site‐specifically organize legumain‐activatable melittin pro‐peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi‐type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.

Development of a novel computational technique to create DNA and cell geometrical models for Geant4-DNA

BackgroundThis study aimed to develop a novel human cell geometry for the Geant4-DNA simulation toolkit that explicitly incorporates all 23 chromosome pairs of the human cell. This approach contrasts with the existing, default human cell, geometrical model, which utilizes a continuous Hilbert curve. MethodsA Python-based tool named “complexDNA” was developed to facilitate the design of both simple and complex DNA geometries. This tool was employed to construct a human cell geometry with individual pairs of chromosomes. Subsequently, the performance of this chromosomal model was compared to the standard human cell model provided in the “molecularDNA” Geant4-DNA example. ResultsSimulations using the new chromosomal model revealed minimal discrepancies in DNA damage yield and fragment size distribution compared to the default human cell model. Notably, the chromosomal model demonstrated significant computational efficiency, requiring approximately three times less simulation time to achieve equivalent results. ConclusionsThis work highlights the importance of incorporating chromosomal structure into human cell models for radiation biology research. The “complexDNA” tool offers a valuable resource for creating intricate DNA structures for future studies. Further refinements, such as implementing smaller voxels for euchromatin regions, are proposed to enhance the model’s accuracy.