DNA Nanocages: Synthetic Organelles Redefine Cellular Engineering!

Artificial cells are the holy grail of syn-bio. But what if we could solve some problems by thinking smaller? Let’s check out synthetic organelles today!

Today “special edition” on Friday! I was busy these days, wedding and traveling to Italy and all. But next week we’ll be back to normal scheduling, every Thursday!

Organelles, One Cage at a Time

Synthetic Cells: the Next Frontier

Synthetic cells are one of the coolest frontiers in synthetic biology.

Engineering cells from scratch would give us incredible control over biological systems and open up new avenues for drugs, new materials, new sensors, and more! The possibilities are (almost) endless.

But cells are complicated.

So, researchers are starting smaller by mimicking organelles. These cellular compartments specialize in one function and handle everything from energy production to waste recycling.

Organelles: Functional, Complicated Compartments

You already know the nucleus, mitochondria, and ribosomes, but we’re constantly discovering new organelles! Each has its own function and structure, and they work together to maintain the cell’s survival and efficiency.

Communication between organelles is strictly organized, and this organization keeps the cell alive and balanced. Understanding it and learning to mimic organelles could be the starting point to design artificial systems that can surpass natural systems!

But we’re still far.

Natural organelles use membrane contact sites (MCSs) and cytoskeletal scaffolds to communicate and exchange signals. Synthetic compartment systems, like lipid vesicles or polymer aggregates, lack the mechanical support and the programmable contact-regulated behaviors of cells.

Could DNA nanotech help bridge this gap?

Empowering EVs with DNA Nanocages

The authors of today’s paper set out to do just that.

They used DNA nanotechnology to build crosslinked “nanocages” on extracellular vesicles (EVs), the tiny, lipid-bound particles that cells naturally release. The cages strengthened the EV membranes, prevented fusion while preserving small-molecule exchange, and enabled programmable communication between compartments!

In short, the EV-DNA cages mimic how real organelles talk to each other! But how do they work?

Building Cages On EVs

The process happens in 2 steps:

1. EVs Preparation and DNA Attachment
   The team isolated EVs from breast cancer cells and incubated them with a cholesterol-modified DNA tetrahedron. The cholesterol anchors one of the tetrahedron’s vertices to the EV membranes, with the other 3 vertices displaying single-stranded DNA (ssDNA) initiators.

2. Nanocages Growth

   Two DNA hairpins open the initiators and trigger a chain reaction, growing 3D DNA nanowires radiating from each tetrahedron. The nanowires can connect and crosslink, growing into a sparse DNA cage.

The authors confirmed the formation of the DNA nanocages using fluorescent microscopy and cryo-EM!

Nanocages and Membrane Mechanics

Membrane stiffness and fluidity determine the stability of lipid vesicles to maintain individual compartments.

Do they change after cage formation?

The authors studied the stiffness of EVs-DNA cages using atomic force microscopy (AFM). In this AFM nanoindentation experiment, the tip of the AFM is pushing on the sample, measuring mechanics at the nanoscale. Crazy!

In this case, the team found that the EVs-DNA cages were 3.7 times stiffer than “naked” EVs!

Then, using fluorescence recovery after photobleaching, they showed that lipid mobility dropped: the cages “locked” the membrane in place.

So, the nanocages add strength and stability, just like a flexible exoskeleton.

Functional Consequences: Stability vs Communication

Natural organelles and vesicles communicate using contact interactions mediated by proteins.

In synthetic systems, this is hard to replicate: once the lipid vesicles meet, they fuse, which leads to unwanted mixing! Can the DNA cage help?

The researcher extended the EVs with ssDNA handles, and the vesicles formed networks of connected EVs. Compared to naked EVs, the caged EVs didn’t fuse, and they were far more stable: up to 72 hours! All while still letting small molecules pass through.

This means these cages preserve metabolic-like exchange while improving structural order: just like natural organelles!

Programmable Networking

I love the idea of creating nanoscale factories by chaining compartments with different enzymes! And the authors did something similar to demonstrate the programmability of the system.

They loaded 3 EV populations with different enzymes:

• Glucose oxidase (GOX)

• Horseradish peroxidase (HRP)

• Catalase (CAT).

Each population had an identity-specific surface DNA chain (La, Lb, Lc), and short connector strands determined which compartments interacted. Different interactions create different enzymatic networks!

The team tested 3 systems.

1. Stochiometry controls the pathway: Varying the connections between populations toggles which enzyme pairs contact and how much product is created. The production varies from low to high, passing through medium, proving spatially encoded routing of metabolites!

2. Autonomous, pH-based feedback: The activity of GOX lowers the pH (from 8 to 4 in 2 hours). pH-sensitive DNA strands trigger decoupling of selected partners, dynamically redirecting the flow of H₂O₂.

3. Sequential “seesaw” logic: A designed A-B-C seesaw circuit causes ordered contact rearrangements (A-B couple at pH 8 → acid triggers i-motif on A → AB dissociates → B binds C), controlling the kinetics of production!

Towards Synthetic Organelle Networks

Cool work!

It’s a step towards synthetic organelle networks that can be feedback-controlled, just like natural ones. It will be valuable for synthetic biology and smart materials, with sensing capabilities!

The new system has:

• Sparse crosslinked topology: The DNA cage balances mechanical reinforcement and permeability (unlike dense coatings).

• Modularity: The whole system is plug-and-play (just change sequences).

• Functional demonstrations: They have shown quantitative enzyme cascade routing and autonomous feedback!

It does have limitations:

• Slow dynamics

• No metabolic coupling to living cells yet

• Possible immunogenicity if used directly in vivo

A cool work! Read all the details here.

If you made it this far, thank you! Do you see a future for SynBio? What do you think could be the next big target? Reply and let me know!

More Room:

• Putting a Lid on DNA Origami: Boxes are one of the OG DNA origami designs. This paper presents a fully enclosed, hollow DNA origami box with two lids designed for controlled cargo encapsulation and release. The structure enables charge-dependent passive loading of small molecules. By adding staple extensions, the box can be customized for protein loading or surface functionalization, making it a versatile platform for targeted drug delivery and nanoscale storage applications.

• Locking Nucleic Acid: Locked nucleic acids (LNA) are a cool tool in the DNA toolbox. This modification changes the characteristics of nucleic acids in DNA, with cool functions. This study introduces a strategy to control DNA self-assembly by tuning base-stacking interactions using LNA modifications. Incorporating LNA into sticky ends reduces base-pair spacing and strengthens stacking energy, enhancing strand affinity and speeding up hybridization. Combining experiments and simulations, the authors show that this approach enables precise control over DNA crystal growth and morphology.

• DNA Heat Engines: Do you want a DNA-based car? Maybe one day. In the meantime, this study presents a microheater-controlled system that dramatically boosts the speed and force of DNA-based machines. By rapidly heating and cooling DNA origami structures within milliseconds, the device enables synchronized hybridization and dehybridization of sticky ends across multiple components. This coordination allows DNA machines to move cooperatively, generating stronger, faster motions. In demonstrations, the system achieved folding speeds over 30 µm/s!

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