Structures determine the efficacy and safety of nanomedicines and promote therapeutic innovation, scientists say

Historically, most medicines have been meticulously designed to the atomic level. The specific position of each atom within a drug molecule is an important factor in determining how well it works and how safe it is. For example, in ibuprofen, one molecule is effective as an analgesic, but mirror images of the same molecule are completely inactive.

Currently, scientists at Northwestern University and the popular general Brigham argue that this precise structural control applied to traditional medicines should be exploited to guide a new class of powerful nanomedicines that can treat some of the world’s most debilitating diseases.

In current nanomedicines, such as mRNA vaccines, the two particles are not the same. To ensure that all nanomesins in the same batch are consistent, and the most powerful version, scientists are devising new strategies to accurately adjust the structure.

This level of control allows scientists to fine-tune how nanomedicines interact with the human body. These new designs lead to powerful vaccines or even treatments for cancer, infectious diseases, neurodegenerative diseases, and autoimmune diseases.

The perspective entitled “The Emerging Era of Structural Nanomedicine” is published in Nature Reviews Bioengineering.

“Historically, most drugs have been small molecules,” said Chad A. Mirkin of Northwestern.

“In the age of small molecules, it was important to control the arrangement of all atoms and all bonds within a particular structure. If one element is out of place, it could negate the entire drug.

“Now we need to bring that tight control to nanomedicine. Structural nanomedicines can design more effective, more effective, more effective, and more beneficial interventions by focusing on the complex details of therapeutic agents and how different medicinal ingredients appear within a larger structure.”

Issues for “blender approach” to vaccine design

Traditional approaches to vaccine design rely primarily on a mix of key components. For example, a typical cancer immunotherapy consists of a molecule or molecule of tumor cells (called antigens) in combination with molecules that stimulate the immune system (called adjuvants). The doctor mixes the antigen and adjuvant into the cocktail and injects the mixture into the patient.

Milkin calls this the “blender approach.” This means that the components are not completely structured. In contrast, structural nanomedicines can be used to organize antigens and adjuvants. When constructed at the nanoscale, these same medicinal ingredients have improved efficacy and reduced side effects compared to the unstructured version. However, unlike small molecule drugs, these nanomedicines are still inaccurate at the molecular level.

“The two drugs in a batch are not the same,” Milkin said.

“Nanoscale vaccines have different lipid counts, different lipids, different RNA levels, different particle sizes. There are infinite variables in nanomedicin formulations. Inconsistencies lead to uncertainty.

Moving from cooperatives to molecular accuracy

To address this issue, Mirkin, Mrksich, and Artzi advocate for a more accurate transition to structural nanomedicine. In this approach, researchers construct nanomedicines from chemically well-defined core structures that can be accurately designed with multiple therapeutic components in controlled spatial arrangements.

Controlling design at the atomic level allows researchers to unlock unprecedented features such as integrating multiple functions into a single drug, optimised target engagement, and triggering drug release in specific cells.

In the paper, the authors cite three examples of pioneering structural nanomedicine: spherical nucleic acids (SNA), chemical spheres, and megaliths.

Invented by Mirkin, SNA is a globular form of DNA that can easily enter cells and bind to targets. SNAS, which is more effective than linear DNA of the same sequence, demonstrates important potential for gene regulation, gene editing, drug delivery, and vaccine development.

“The overall structural presentation of an SNA-based vaccine or treatment has proven that it dramatically affects its efficacy rather than simply an active chemical component,” Milkin said.

“This finding could lead to treatment of many different types of cancer. In certain cases, this could be used to cure patients that could not be treated with other known treatments.”

Chemical spheres pioneered by Artzi and Mirkin are smart nanostructures that release chemotherapeutic drugs in response to disease-related cues in cancer cells. Invented by Mrksich, Megamolecules are precisely assembled protein structures that mimic antibodies. Researchers can design all these types of structural nanomedicines to carry multiple therapeutic or diagnostic tools.

“By leveraging disease-specific tissue and cellular cues, next-generation nanomedicine can achieve highly localized and timely drug release.

“This level of accuracy is particularly important for combination therapy where coordinated delivery of multiple agents reduces systemic toxicity and dramatically improves treatment efficacy while minimizing target-off effects. Such a smart and responsive system represents an important advance in overcoming the limitations of traditional drug delivery.”

Use AI in design

Going forward, researchers will need to address current challenges in scalability, reproducibility, delivery and integrating multiple therapeutic agents, the authors say. The authors also highlight the increasingly important role of emerging technologies such as machine learning and artificial intelligence (AI) in optimizing design and delivery parameters.

“If you look at the structure, there are tens of thousands of possibilities for how components can be placed on nanomedicines,” Milkin said.

“AI allows you to narrow down to just a handful of lab-synthetic sets of irregular structures to synthesize and test them. By controlling the structure, you can create the most powerful drugs with the lowest possible side effects.

“We can reconstruct medicinal ingredients such as nucleic acids to create entities with properties that go far beyond what we’ve seen in standard DNA and RNA. This is just the beginning and we’re excited to see what’s next.