Nature-inspired RNA delivery

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Today, we are exploring one of the most exciting topics around: nanomedicine!

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Nature-inspired RNA delivery

Just a few weeks ago, we explored how nanotechnology enables targeted drug delivery, helping drugs reach specific cells or organs while reducing side effects. One of the most promising new category of drugs is nucleic acid-based therapeutics, which allow to precisely regulate gene expression. There are a few major types:

• mRNA: Just like the COVID vaccines, mRNA instructs cells to produce proteins, useful for treating genetic deficiencies or generating immunity.

• Short interfering RNA (siRNA): These small molecules bind to mRNA inside cells, stopping its function and preventing harmful protein overproduction!

• Antisense oligonucleotides (ASO): Short sequences that bind to complementary RNA, modifying gene expression at the RNA splicing level.

But there’s a problem: nucleic acid drugs degrade rapidly in the body. To protect them, they are typically encapsulated into lipid nanoparticles (LNPs), tiny spheres made of lipids. LNPs are great for protecting the drugs, but they have a major limitation: they mostly accumulate in the liver (the great filter of the body), making it difficult to target other tissues. This has made them successful in applications such as vaccines and gene therapies, but not much else.

This is where today’s paper comes in: the researchers developed a new, nature-inspired platform to deliver nucleotide drugs to immune cells outside of the liver!

Apolipoprotein nanoparticles (aNPs) to deliver RNA drugs

The team designed a new system based on lipoproteins, the body’s natural carriers of fats in the bloodstream. Specifically, they focused on apoA1, the main component of high-density lipoproteins (HDL), responsible for transporting cholesterol in the body and that naturally interacts with immune cells.

The researchers first designed a prototype apolipoprotein nanoparticle (aNP) to encapsulate siRNA and tested its ability to:

• Specifically deliver siRNA to bone marrow and spleen, key sites for immune regulation

• Protect the siRNA and enable gene silencing, proving that the drug remains functional

To optimize the properties of the particles, they created a library of 72 aNP formulations, varying:

• Phospholipids: for stability and membrane interaction

• Cholesterol derivatives: to enhance cellular uptake

• Ionizable lipids: to facilitate RNA release into cells

After screening, the researchers had found 8 formulations (including the prototype) that exhibited high RNA encapsulation efficiency, stability and silencing efficacy, and moved to test them in mice.

aNPs for cancer immunotherapy

The team used aNPs to silence the lysosomal associated membrane protein 1 (Lamp1) gene in immune cells. The results were impressive:

• The best-performing formulation, aNP18, achieved strong gene silencing in bone marrow white blood cells, which are involved in the immune response).

• Unlike LNPs, which mostly accumulate in the liver, aNP18 preferentially targeted the bone marrow and spleen.

• Overall, aNPs outperformed conventional LNPs in both targeting and gene knockdown efficiency.

A major challenge in cancer treatment is the presence of immunosuppressive cells in tumors, which help cancer evade the immune system. The researchers tested aNP18 loaded with siRNA against CCr2, a key gene involved in recruiting tumor-associated macrophages that suppress the immune system. When they administered aNP18 to tumor-bearing mice, the nanoparticles successfully reduced the number of CCR2 positive immune cells in the tumor, without negative side effects. These cells contribute to immune evasion by the cancer: reducing their numbers could make the tumor more susceptible to therapies! For example, they could be used in combination with immune checkpoint inhibitors therapies, a major strategy in modern cancer treatment.

Beyond siRNA: ASOs and mRNA, and more

The researchers were not satisfied with just siRNA, so they expanded their study to other RNA therapeutics:

• ASOs: The aNPs efficiently delivered ASOs to immune cells in the bone marrow: here, the nanoparticles modulated gene expression at the RNA splicing level.

• mRNA: Everyone’s favorite, since 2020. The team successfully delivered mRNA encoding GFP, confirming that aNPs could be used for mRNA therapies.

These experiments show the versatility of their approach, making aNPs suited to deliver different RNA therapeutics to immune cells. This could open new possibilities for treating a range of diseases, including:

• Inflammatory and autoimmune disorders: aNPs could help control excessive immune responses in conditions like rheumatoid arthritis.

• Cancer immunotherapy: As we have seen, aNPs can target immunosupressive immune cells, so they can be used to enhance the immune response against tumors.

• Regenerative medicine: The nanoparticles could deliver RNA therapeutics to the bone marrow progenitors to promote tissue repair.

To wrap it up, this was a great advancement for lipid-based nanotechnology and for RNA therapeutics! Improving the targeting of drugs opens up a lot of avenues for the field. This paper goes in a lot of details, and you can read them here!

And as always, thank you for reading! What are your thoughts on lipid nanoparticles in drug delivery and on this paper? Reply and let me know!

More room:

• DNA, crystals and gold: It’s not the title of the next Indian Jones: this study uses DNA origami to self-assemble chiral rhombohedral crystals, later modified with gold nanorods to create plasmonic metamaterials active in the visible and near-infrared range. The researchers demonstrate chiral optical activity, showcasing DNA origami’s potential in photonic material design

• Don’t underestimate DNA pol: Because it’s always more complicated. DNA pol δ is a key enzyme for DNA replication in eukaryotes, and this paper presents the cryo-EM structure of apo-form human DNA polymerase δ (Pol δ) at 3.65 Å resolution, revealing how its activity is regulated. Cool images as usual!

• Expanding microscopy even more: Expansion microscopy is an ingenious technique that physically magnifies preserved samples by using an expandable polymeric network. This study builds on it, allowing high-density membrane labelling and nanoscale imaging. This study achieves 35 nm, bringing electron microscopy-like visualization to light microscopes. Insane!

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