Thanks, Dr. Aartsma-Rus, for featuring our study and providing a great breakdown of the work! Really appreciate your thoughtful comments.

One small clarification: we did include a mock-PMO treated control to account for non-specific effects.

The use of mRNA in medicine is growing quickly. This study further emphasizes the necessity of understanding how these particles travel in vivo and interact with the immune system to advance precision medicine.

For me, as someone working with LNPs to deliver synthetic genetic materials, this study backs an important reality—we need better delivery strategies. Whether for vaccines, gene therapies, or RNA therapeutics, refining LNP design is key to maximizing efficacy and minimizing unintended effects.

This study demystifies how mRNA vaccines spread in the body, confirming that LNPs effectively reach immune hubs while avoiding major off-target accumulation. But at the same time, it leaves critical gaps unanswered.

LNP behaviour is known to be species-dependent, yet most biodistribution studies rely on rodent models. While rhesus macaques offer a closer parallel, how well do these findings translate to humans?

I would love to see comparative studies of IM vs. IV administration, as they could be essential to understanding these dynamics.

For gene addition and editing, IV delivery is often the most feasible. However, systemic circulation can significantly affect LNP biodistribution, leading to:
→ Increased liver accumulation
→ Potential cardiac exposure
→ Differential immune engagement, like spleen uptake vs. lymphatic processing

While this study offers important insights into intramuscular (IM) mRNA vaccine delivery, it raises bigger questions for gene therapy applications, particularly those requiring intravenous (IV) delivery.

This aligns with existing knowledge, the study doesn’t explore whether different LNP formulations alter which immune cells preferentially take up nanoparticles. Would tweaking lipid composition change cellular tropism? This could be crucial for boosting immune targeting or reducing inflammation.

Once inside the lymph nodes, LNPs are primarily taken up by antigen-presenting cells (APCs):

→ Dendritic cells → Key for presenting antigens to T cells

→ Monocytes & neutrophils → Early responders influencing inflammation

I guess this is a major consideration, especially as LNPs are being investigated for chronic treatments like gene therapies.

Actually, liver accumulation isn’t surprising—hepatic clearance is a known clearance pathway for LNPs—but what does this mean for long-term safety? Could repeated dosing in therapeutic applications lead to immune modulation or hepatotoxicity?

...that there was minimal off-target distribution, but the liver remains a wildcard!

→ Little to no LNP accumulation in the heart, lungs, or brain (great!)
→ Noticeable LNP presence in the liver, albeit lower than in lymph nodes (not good)

One of the most pressing concerns with LNP-based drug delivery is off-target accumulation. Ideally, LNPs should stay localized to muscle and lymph nodes, ensuring a strong immune response without unnecessary systemic exposure. They found...

So, could this (partially) explain why vaccine efficacy sometimes fluctuates between recipients?

This finding is both reassuring and concerning. It confirms that LNPs effectively reach key immune sites. But it also raises questions about stochastic lymphatic drainage, a factor that could introduce variability in immune response across individuals.

They report that LNPs rapidly reach immune hubs, but transport is variable:
→ Deltoid injections targeted the axillary, apical, and pectoral lymph nodes
→ Quadriceps injections reached the iliac lymph nodes

This study tackled these questions by radiolabeling LNPs and tracking their movement post-injection. They found that just in 4 hours, a big portion had already drained into lymph nodes (dLNs)—indicating that passive lymphatic transport, rather than active immune cell uptake, plays the dominant role.

Since the global rollout of LNP-based COVID-19 mRNA vaccines, LNP-based drug delivery has gained traction, but there are still major knowledge gaps in their in vivo behaviour, particularly regarding systemic circulation, clearance, and immune cell interactions.