Historically, the vast majority of pharmaceutical drugs have been meticulously designed down to the atomic level. The specific location of each atom within the drug molecule is a critical factor in determining how well it works and how safe it is. In ibuprofen, for example, one molecule is effective as a pain reliever, but the mirror image of that same molecule is completely inactive.
Now, Northwestern University and Mass General Brigham scientists argue that this precise structural control, which is applied to traditional medicines, should be harnessed to usher in a new class of potent nanomedicines that can treat some of the world’s most debilitating diseases.
With current nanomedicines like the mRNA vaccines, no two particles are the same. To ensure that all nanomedicines in the same batch are consistent—and the most potent versions—scientists are devising new strategies to precisely tailor their structures.
With this level of control, scientists can fine-tune how nanomedicines interact with the human body. These new designs are leading to potent vaccines or even cures for cancers, infectious diseases, neurodegenerative diseases and autoimmune disorders.
The perspective, titled “The emerging era of structural nanomedicine,” is published in the journal Nature Reviews Bioengineering.
“Historically, most drugs have been small molecules,” said Northwestern’s Chad A. Mirkin, who coauthored the paper.
“In the small molecule era, it was critical to control the placement of every atom and every bond within a particular structure. If one element was out of place, it might render the whole drug ineffective.
“Now, we need to bring that tight control to nanomedicine. Structural nanomedicine represents a massive shift in how we can approach therapeutic development. By focusing on the intricate details in our therapeutics and how different medicinal components are displayed within a larger structure, we can design interventions that are more effective, more targeted and, ultimately, more beneficial for patients.”
Problems with ‘the blender approach’ to vaccine design
In conventional approaches to vaccine design, researchers have mostly relied on mixing key components together. Typical cancer immunotherapies, for example, consist of a molecule or molecules from tumor cells (called antigens) paired with a molecule (called an adjuvant) that stimulates the immune system. Physicians mix the antigen and adjuvant together into a cocktail and then inject the mixture into the patient.
Mirkin calls this the “blender approach”—in which the components are completely unstructured. In stark contrast, structural nanomedicines can be used to organize antigens and adjuvants. When structured at the nanoscale, those same medicinal components exhibit enhanced efficacy and decreased side effects compared to unstructured versions. However, unlike small molecule drugs, these nanomedicines are still imprecise at the molecular level.
“No two drugs in a batch are the same,” Mirkin said.
“Nanoscale vaccines have different numbers of lipids, different presentations of lipids, different amounts of RNA and different sizes of particles. There are an infinite number of variables in nanomedicine formulations. That inconsistency leads to uncertainty. There’s no way to know if you have the most effective and safest construct among the vast number of possibilities.”
Moving from co-assembly to molecular precision
To address this problem, Mirkin, Mrksich and Artzi advocate for a shift toward even more precise structural nanomedicines. In this approach, researchers build nanomedicines from chemically well-defined core structures that can be precisely engineered with multiple therapeutic components in a controlled spatial arrangement.
By controlling design at the atomic level, researchers can unlock unprecedented capabilities, including the integration of multiple functionalities into one drug, optimized target engagement and triggered drug release in specific cells.
In the paper, the authors cite three examples of trailblazing structural nanomedicines: spherical nucleic acids (SNAs), chemoflares and megamolecules.
Invented by Mirkin, SNAs are a globular form of DNA that can easily enter cells and bind to targets. More effective than linear DNA of the same sequence, SNAs have demonstrated significant potential in gene regulation, gene editing, drug delivery and vaccine development—even in certain cases curing deadly forms of skin cancer in a clinical setting.
“We have proven that the overall structural presentation of an SNA-based vaccine or therapeutic—not simply the active chemical components—dramatically affects its potency,” Mirkin said.
“This finding could lead to treatments for many different types of cancer. In certain cases, we’ve used this to cure patients who could not be treated with any other known therapy.”
Pioneered by Artzi and Mirkin, chemoflares are smart nanostructures that release chemotherapeutic drugs in response to disease-related cues in cancer cells. And megamolecules, invented by Mrksich, are precisely assembled protein structures that mimic antibodies. Researchers can engineer all these types of structural nanomedicines to carry multiple therapeutic agents or diagnostic tools.
“By harnessing disease-specific tissue and cellular cues, next-generation nanomedicines can achieve highly localized and timely drug release—transforming how and where therapies act within the body,” Artzi said.
“This level of precision is especially critical for combination treatments, where coordinated delivery of multiple agents can dramatically enhance therapeutic efficacy while reducing systemic toxicity and minimizing off-target effects. Such smart, responsive systems represent a crucial step forward in overcoming the limitations of conventional drug delivery.”
Harnessing AI in design
Going forward, researchers will need to address current challenges in scalability, reproducibility, delivery and multiple therapeutic agent integration, the authors say. The authors also highlight the increasingly important role of emerging technologies like machine learning and artificial intelligence (AI) in optimizing design and delivery parameters.
“When looking at structure, there are sometimes tens of thousands of possibilities for how to arrange components on nanomedicines,” Mirkin said.
“With AI, we can narrow down giant sets of unexplored structures to a handful to synthesize and test in the lab. By controlling structure, we can create the most potent medicines with the lowest chance of side effects.
“We can restructure medicinal components like nucleic acids to create entities that have properties that go so far beyond what we have ever seen with standard DNA and RNA. This is just the beginning, and we’re excited to see what’s next. We are poised to usher in an entire new era of structural medicine, with Northwestern taking the lead.”
