Cloak and Cure: Disguising Nanoparticles as Immune Allies

by Lucia Wesemann
figures by Fiona Qu

Think about the last time you took a simple pain reliever for a lingering headache or a course of antibiotics to tackle an infection. Have you ever wondered how these medications move through your body? Or if they are even able to aim for the exact location in need of healing? In reality, most drugs travel through your entire system, often triggering side effects along the way that can feel as unsettling as the original complaint. Now imagine if your medication could travel directly to the source of your problem. What if unpleasant side effects could be a thing of the past? This is the intriguing promise of nanoparticles: an innovative solution at the tiniest scale. These nanoparticles act like precise delivery vehicles that could one day revolutionize how we treat diseases, delivering drugs to specific tissues without affecting the rest of the body. While there are many significant barriers to nanoparticle-based drug delivery, creative solutions are on the horizon.

The Challenge of Traditional Drug Delivery

Many medications are delivered via the traditional route, where the drug spreads throughout the entire body and its effects can be felt systemically. Therefore, for most patients, receiving treatment isn’t just about fighting the disease – it is also about enduring the side effects. Chemotherapy, for example, fights cancer by attacking the fast-growing tumor cells and interrupting the process of cell division. However, because chemotherapy is administered directly into the bloodstream, the drugs travel throughout the body, attacking fast growing cells everywhere, whether they are tumor cells or healthy cells such as those of hair follicles or cells lining the gut. The result? Patients experience severe side effects: unrelenting nausea, vomiting, hair loss, fatigue, and even nerve damage and paralysis. These side effects not only impact their quality of life, but can be overwhelming to the extent that medication dosages need to be reduced or delayed.

This challenge of targeted drug delivery isn’t unique to cancer. The medications for many diseases can cause crippling complications that limit the effectiveness of treatment. This has created an urgent need for smarter drug delivery systems across fields of medicine.

The Promise of Nanoparticles

Enter nanoparticles: powerful, tiny materials that can act as drug carriers. These nanoparticles can be loaded with any drug and “programmed” to precisely deliver it to the intended tissue in the body – like typing coordinates into a GPS.

How, then, do these nanoparticles work? The surfaces of nanoparticles can be coated with specific markers – tiny molecular “tags” – that act like a homing device, directing them to the correct tissue. This targeted approach is far more precise than the release of a flood of tiny drug molecules throughout the entire body. For instance, chemotherapy-filled nanoparticles could be essentially signed, sealed, and delivered straight to a tumor, bypassing healthy cells and therefore the toxic side effects. Many nanoparticle-based therapies are currently being tested in clinical trials.

Nanoparticles and Immune Defense

Despite their potential, nanoparticles face a significant hurdle in transporting medications to the proper location in the body: the immune system. The immune system is responsible for keeping us safe from harmful trespassers, including bacteria, viruses, and parasites. While this system protects us from disease-causing foreign invaders, it can also destroy nanoparticles, inhibiting effective drug delivery. If the immune system is meant to protect us from harm, why doesn’t it ensure the safe passage of lifesaving drugs to their intended target? And how do our immune cells, the foot soldiers of the immune system, discern what is “self” and what is “foreign”?

Special molecules on the surface of immune cells enable them to decide what to attack and what to leave intact. Certain immune cells specifically target any entity that is not decorated with special “self” signals, which are present on the surface of all healthy cells in your body (Figure 1). Nanoparticles naturally lack these signals, prompting immune cells to recognize them as foreign. This reduces the efficacy of the drugs carried by the nanoparticles, since they are less likely to make it to the desired site. Overcoming this challenge has required unique and creative strategies to make nanoparticles functionally invisible to the immune system.

**Figure 1:** Detection of “self” signals on the surface of cells by macrophages to identify foreign particles.

A Nanoparticle in Macrophages Clothing

Scientists have found a clever way to sneak nanoparticles past our immune system by camouflaging them to look like immune cells. One type of immune cell – called a macrophage, or “big eater” – has been well-studied using this technique. Drug-carrying nanoparticles are coated with an outer cell layer, or membrane, identical to that of macrophages that essentially hides them from our immune defenses. It’s as if these nanoparticles are pulling off a daring heist, breaking into a building by wearing security uniforms and ID badges to sneak past the guards. But instead of stealing anything, this heist team is there to make repairs.

There are several capabilities of macrophages that make them ideal membrane donors. Most importantly, macrophages are always recognized by the immune system as “self”. The consequence? The immune system leaves them alone. Secondly, macrophage membranes contain built-in sensors that guide them like magnets to sites of damage or inflammation. So when supplemented with tumor-sensing molecules, macrophage membrane-coated nanoparticles have no trouble infiltrating and killing cancer cells (Figure 2). Finally, cloaking nanoparticles in this protective layer helps them last longer in circulation, allowing more time for trafficking to the correct location.

**Figure 2:** Macrophage-membrane coated nanoparticles are able to sneakily bypass the body’s immune defenses to precisely deliver their cargo to the intended target. This happens because immune cells recognize these camouflaged nanoparticles as “self” rather than “foreign.” In contrast, bare nanoparticles are much more likely to be recognized and captured by immune cells, blunting their effectiveness.

Looking to the Future

While these cleverly camouflaged nanoparticles have only been tested in animal models of disease so far, the results have been promising. One study found that an anti-cancer drug was more effective at shrinking deadly tumors in mice when it was delivered in macrophage membrane-coated nanoparticles, as compared to uncoated nanoparticles. It is imperative that researchers address safety considerations and conduct robust clinical trials before this technology can be widely used in patients. With continued testing, this creative strategy could revolutionize drug delivery, offering safer and more effective treatment for a wide range of diseases.

Lucia Wesemann is a first-year PhD student in the Immunology PhD program at Harvard University.

Fiona Qu is a PhD candidate in the Systems, Synthetic, and Quantitative Biology program at Harvard.

Cover image by Pexels on pixabay.

For More Information:

To read more about current nanoparticle-based therapies in clinical trials for the treatment of different cancers, click here.
For a deep dive into the role of macrophages in immune defense, here is a great YouTube video by Professor Dave Explains: Macrophages: The Destroyers.
Here is a broad review on the interactions between nanoparticles and the immune system.