About

Professor Mark Bathe is a faculty member of the Department of Biological Engineering at MIT. He obtained his Bachelor’s, Master’s, and Doctoral Degrees from MIT, working in the Departments of Mechanical, Chemical, and Biological Engineering. After completing his degrees, he carried out postdoctoral research at the University of Munich. He returned to MIT in 2009 to join the faculty, where he leads an interdisciplinary research group focused on the use of nucleic acids as highly programmable nanoscale materials for revolutionary applications including targeted in vivo delivery of therapeutic nucleic acids, molecular data storage, retrieval, and computing, as well as quantum computing and sensing. His lab develops design and fabrication procedures based on principles of nucleic acid nanotechnology, which allows for the programming of RNA and DNA to form complex, custom nanoscale materials with unique synthetic properties. These materials are fully controllable in their 2D and 3D structures and can incorporate various secondary molecules such as peptides, lipids, sugars, chromophores, and synthetic polymers for functional purposes. His research explores designing, fabricating at high scale and quality, and validating these nucleic acid-based materials both in vitro and in vivo, aiming for the discovery and commercial translation of new materials to address societal challenges. Professor Bathe is also a member of the HMS Initiative for RNA Medicine and an associate member of the Broad Institute of MIT & Harvard.

Research topics

• Computational biology
• Materials science
• Biology
• Chemistry
• Nanotechnology
• Computer Science
• Cell biology
• Operating system
• Biochemistry
• Genetics
• Theoretical computer science
• Biophysics
• Virology
• Medicine
• Optoelectronics

Selected publications

• Programmable Lipid Functionalization of Nucleic Acid Nanoparticles Modulates Liver Cell-Type Targeting

  ACS Applied Materials & Interfaces · 2026-03-25

  articleOpen accessSenior authorCorresponding

  Nucleic acid nanoparticles (NANPs) fabricated by using DNA origami are an emerging delivery vector for nucleic acid therapeutics. Despite their advantages over other nanomaterials that include controlled spatial presentation of targeting ligands such as lipids and sugars, understanding their cell targeting and uptake mechanisms remains limited. Here, we investigated NANP cellular targeting, uptake, and delivery of small interfering RNAs (siRNAs) to liver and neuronal cell models in vitro. Using a rational design approach, we targeted NANPs to two clinically validated receptors, the asialoglycoprotein receptor (ASGPR) and the low-density lipoprotein receptor (LDLR), respectively, using GalNAc and lipidation. We systematically evaluated how the ligand valency, interligand spacing, linker length, and ligand chemistry affected NANP association with on- and off-target liver cell types, revealing the relative roles of the biomolecular corona, receptor engagement, and endocytosis in these targeting strategies. We found that lipidation enhanced NANP uptake into HepG2 cells, a model cell line for hepatocytes, by promoting apolipoprotein recruitment, LDLR engagement, and clathrin-mediated endocytosis and also increased association with nonparenchymal cells. HepG2 uptake was further improved by conjugating NANPs to lipids with higher valency provided that lipids were adequately displayed away from the surface of NANP edges with more lipophilic lipids yielding greater cell association. We then benchmarked the potential for NANPs to deliver siRNAs to HepG2 cells in comparison with lipid nanoparticle and conjugate technologies and explored lipid functionalization as a strategy for nonhepatic NANP targeting to model neuronal cells. Overall, this study advances the foundational understanding of how clinically relevant targeting ligands mediate NANP interactions with both on- and off-target liver cell types in vitro, offering insights into potential design criteria for nucleic acid therapeutic delivery.

  PublisherDOI

• DNA origami vaccines program antigen-focused germinal centers

  Science · 2026-02-05 · 6 citations

  article

  Priming rare subdominant precursor B cells in germinal centers (GCs) is a central goal of vaccination to generate broadly neutralizing antibodies (bnAbs) against HIV. Multivalent immunogen display on protein nanoparticle scaffolds can promote such responses, but it also generates scaffold-specific B cells that could theoretically limit bnAb precursor expansion in GCs. We rationally designed DNA origami-based virus-like particles (DNA-VLPs) displaying a germline-targeting HIV envelope protein immunogen, which elicited no scaffold-specific antibody responses. Compared with a state-of-the-art clinical protein nanoparticle, these DNA-VLPs increased the expansion of epitope-specific GC B cells relative to off-target B cells and enhanced expansion of bnAb-lineage B cells in a humanized mouse model of CD4 binding site priming. Thus, minimizing off-target responses enhances bnAb priming and indicates that DNA-VLPs are a promising vaccine platform.

  PublisherDOI

• Enabling global-scale nucleic acid repositories through versatile, scalable biochemical selection from room-temperature archives

  Nature Communications · 2026-02-14

  articleOpen accessSenior authorCorresponding

  Conventional storage and retrieval of nucleic acid specimens, particularly unstable RNA, rely on costly cold-chain infrastructure and inefficient robotic handling, inhibiting large-scale nucleic acid archives needed for global genomic biobanking. We introduce a scalable room-temperature storage system with minimal physical footprint that enables database-like queries on encapsulated, barcoded, and pooled nucleic acid samples. Queries incorporate numerical ranges, categorical filters, and combinations thereof, advancing beyond previous demonstrations of single-sample retrieval or Boolean classifiers. We evaluate this system on ninety-six mock SARS-CoV-2 genomic samples barcoded with theoretical patient data including age, location, and diagnostic state, demonstrating rapid, scalable retrieval. We further demonstrate storage and sequencing of human patient-derived nucleic acid samples, illustrating applicability to clinical genomic analysis. By avoiding freezer-based storage and retrieval, this approach scales to millions of samples without loss of fidelity or throughput, enabling large-scale pathogen and genomic repositories in under-resourced or isolated regions of the US and worldwide. Large biospecimen banks are limited by a lack of fast, flexible, database-like retrieval. Here, authors encode metadata as DNA barcodes on silica-encapsulated samples and demonstrate numerical range, categorical, and Boolean queries, enabling rapid, precise recall from pooled DNA/RNA archives.

  PublisherOA PDFDOI

• Interpretable Deep Learning for Single-Molecule Nanopore Fingerprinting Using Physics-Guided Preprocessing

  ACS Sensors · 2026-02-20

  article

  Rapid and robust molecular fingerprinting is critical in biomanufacturing, diagnostics, and environmental monitoring. Nanopore sensing provides single-molecule readouts as transient ionic current pulses; however, conventional analyses depend on handcrafted features that miss informative structural information. We present an interpretable machine learning framework that operates directly on raw pulses, pairing a physics-guided time-frequency transform with a compact neural classifier and feature-attribution maps. We also include conventional feature-based SVMs and a 1D classifier trained on raw pulses as baselines. On two self-assembled DNA nanostructures of similar size but distinct geometry, for which standard pulse features overlap, the method achieves high accuracy and yields physically consistent attributions that highlight discriminative signal motifs. A matched control without the time-frequency transform clarifies when learned filters suffice versus when physics-guided preprocessing improves reliability, leading to a practical "custom-filter" design principle. The workflow is modular, lightweight, and applicable to pulse-based sensing platforms, including virus and exosome analysis, electrochemical monitoring, and industrial fault detection. By combining accuracy with transparency, it lays the groundwork for deployable sensing platforms in regulated, mission-critical settings.

  PublisherDOI

• Heterovalent Click Reactions on DNA Origami

  Bioconjugate Chemistry · 2025-03-05 · 2 citations

  articleSenior authorCorresponding

  Nucleic acid nanoparticles (NANPs) fabricated by using the DNA origami method have broad utility in materials science and bioengineering. Their site-specific, heterovalent functionalization with secondary molecules such as proteins or fluorophores is a unique feature of this technology that drives its utility. Currently, however, there are few chemistries that enable fast, efficient covalent functionalization of NANPs with a broad conjugate scope and heterovalency. To address this need, we introduce synthetic methods to access inverse electron-demand Diels-Alder chemistry on NANPs. We demonstrate a broad conjugate scope, characterize application-relevant kinetics, and integrate this new chemistry with strain-promoted azide-alkyne cycloaddition chemistry to enable heterovalent click reactions on NANPs. We applied these chemistries to formulate a prototypical chemical countermeasure against chemical nerve agents. We envision this additional chemistry finding broad utility in the synthetic toolkit accessible to the nucleic acid nanotechnology community.

  PublisherDOI

• Transport of Delocalized Excitons through DNA-Based Molecular Photonic Wires

  ACS Nano · 2025-10-29 · 2 citations

  articleCorresponding

  Molecular photonic wires conduct electronic energy via their rapid transport properties. In photosynthesis, nature achieves efficient transport across large distances using delocalized excitons, generated by strong excitonic coupling between chromophores. How, or even whether, delocalization facilitates long-distance energy transport in synthetic systems has been challenging to experimentally test and optimize. Thus, far, studies have been limited to strongly coupled, heterogeneous chromophore aggregates or weakly coupled chromophore monomers. Here, we employed DNA nanostructures to engineer molecular photonic wires constructed from a series of excitonically coupled indocarbocyanine chromophores─achieving the intermediate and strong coupling regimes. Using time-resolved fluorescence spectroscopy and complementary simulations, we demonstrated that an intermediate intermolecular electronic coupling (∼kBT) enables up to 40% faster exciton transport as compared to strongly coupled chromophores. The delocalized excitons generated in the intermediate coupling regime exhibited properties conducive to rapid diffusivity, similar to their monomeric counterparts. Thus, intermediate excitonic coupling, analogous to natural systems, achieves long-distance exciton transport with the high chromophore density required for energy capture.

  PublisherDOI

• Data from: DNA origami vaccines program antigen-focused germinal centers

  Open MIND · 2025-03-24

  dataset

  Priming rare subdominant precursor B cells in germinal centers (GCs) is a central goal of vaccination to generate broadly neutralizing antibodies (bnAbs) against HIV. Multivalent immunogen display on protein nanoparticle scaffolds can promote such responses, but it also generates scaffold- specific B cells that could theoretically limit bnAb precursor expansion in GCs. We rationally designed DNA origami–based virus–like particles (DNA- VLPs) displaying a germline- targeting HIV envelope protein immunogen, which elicited no scaffold-specific antibody responses. Compared with a state- of- the- art clinical protein nanoparticle, these DNA- VLPs increased the expansion of epitope-specific GC B cells relative to off-target B cells and enhanced expansion of bnAb- lineage B cells in a humanized mouse model of CD4 binding site priming. Thus, minimizing off-target responses enhances bnAb priming and indicate DNA- VLPs are a promising vaccine platform.

  DOI

• DNA Origami Nanostructures Observed in Transmission Electron Microscopy Images can be Characterized through Convolutional Neural Networks

  ArXiv.org · 2025-03-13

  preprintOpen access

  Artificial intelligence (AI) models remain an emerging strategy to accelerate materials design and development. We demonstrate that convolutional neural network (CNN) models can characterize DNA origami nanostructures employed in programmable self-assembling, which is important in many applications such as in biomedicine. Specifically, we benchmark the performance of 9 CNN models -- viz. AlexNet, GoogLeNet, VGG16, VGG19, ResNet18, ResNet34, ResNet50, ResNet101, and ResNet152 -- to characterize the ligation number of DNA origami nanostructures in transmission electron microscopy (TEM) images. We first pre-train CNN models using a large image dataset of 720 images from our coarse-grained (CG) molecular dynamics (MD) simulations. Then, we fine-tune the pre-trained CNN models, using a small experimental TEM dataset with 146 TEM images. All CNN models were found to have similar computational time requirements, while their model sizes and performances are different. We use 20 test MD images to demonstrate that among all of the pre-trained CNN models ResNet50 and VGG16 have the highest and second highest accuracies. Among the fine-tuned models, VGG16 was found to have the highest agreement on the test TEM images. Thus, we conclude that fine-tuned VGG16 models can quickly characterize the ligation number of nanostructures in large TEM images.

  PublisherOA PDFDOI

• DNA origami directed nanometer-scale integration of colloidal quantum emitters with silicon photonics

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-26 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Incorporation of colloidal quantum emitters into silicon-based photonic devices would enable major advances in quantum optics. However, deterministic placement of individual sub-10 nm colloidal particles onto micron-sized photonic structures with nanometer-scale precision remains an outstanding challenge. Here, we introduce Cavity-Shape Modulated Origami Placement (CSMOP) that leverages the structural programmability of DNA origami to precisely deposit colloidal nanomaterials within lithographically-defined resist cavities. CSMOP enables clean and accurate patterning of origami templates onto photonic chips with high yields. Soft-silicification-passivation stabilizes deposited origamis, while preserving their binding sites to attach and align colloidal quantum rods (QRs) to control their nanoscale positions and emission polarization. We demonstrate QR integration with photonic device structures including waveguides, micro-ring resonators, and bullseye photonic cavities. CSMOP therefore offers a general platform for the integration of colloidal quantum materials into photonic circuits, with broad potential to empower quantum science and technology.

  PublisherOA PDFDOI

• DNA origami vaccines program antigen-focused germinal centers

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-27 · 8 citations

  preprintOpen access

  Recruitment and expansion of rare precursor B cells in germinal centers (GCs) is a central goal of vaccination to generate broadly neutralizing antibodies (bnAbs) against challenging pathogens such as HIV. Multivalent immunogen display is a well-established method to enhance vaccine-induced B cell responses, typically accomplished by using natural or engineered protein scaffolds. However, these scaffolds themselves are targets of antibody responses, with the potential to generate competitor scaffold-specific B cells that could theoretically limit expansion and maturation of "on-target" B cells in the GC response. Here, we rationally designed T-independent, DNA-origami based virus-like particles (VLPs) with optimal antigenic display of the germline targeting HIV Env immunogen, eOD-GT8, and appropriate T cell help to achieve a potent GC response. In preclinical mouse models, these DNA-VLPs expanded significantly higher frequencies of epitope-specific GC B cells compared with a state-of-the-art clinical protein nanoparticle. Optimized DNA-VLPs primed germinal centers focused on the target antigen and rapidly expanded subdominant broadly neutralizing antibody precursor B cells for HIV with a single immunization. Thus, avoiding scaffold-specific responses augments priming of bnAb precursor B cells, and DNA-VLPs are a promising platform for promoting B cell responses towards challenging subdominant epitopes.

  PublisherOA PDFDOI

Recent grants

• AF Medium: DNA-based Data Storage and Computing Materials

  NSF · $900k · 2020–2025

• AF: Medium: Collaborative Research: Top-down algorithmic design of structured nucleic acid assemblies

  NSF · $638k · 2016–2021

• RAISE-TAQS: Room-Temperature Quantum Sensing and Computation using DNA-based Excitonic Circuits

  NSF · $1.0M · 2018–2023

• DNA Nanoparticle Vaccine for COVID-19

  NIH · $233k · 2020–2020

• EAGER: Collaborative Research: Algorithmic design principles for programmed DNA nanocages

  NSF · $155k · 2015–2019

Frequent coauthors

• Rémi Veneziano

  George Mason University

  28 shared

• Paul C. Blainey

  Broad Institute

  26 shared

• James L. Banal

  24 shared

• Darrell J. Irvine

  Scripps Research Institute

  23 shared

• Nilah Monnier

  Atos (France)

  23 shared

• Syuan-Ming Guo

  Chan Zuckerberg Initiative (United States)

  20 shared

• Tyson R. Shepherd

  20 shared

• Eike‐Christian Wamhoff

  Massachusetts Institute of Technology

  18 shared

Education

• Ph.D., Mechanical Engineering

  Massachusetts Institute of Technology

  2004

• M.Sc., Mechanical Engineering

  Massachusetts Institute of Technology

  2001

• B.Sc., Mechanical Engineering

  Massachusetts Institute of Technology

  1998