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The Next Frontier in Nanomedicine: Structural Precision
Historically, the pharmaceutical industry has focused on designing drugs at an atomic level, where the arrangement of each atom is paramount to a drug’s effectiveness and safety. A prime example is ibuprofen: one molecular structure serves as an effective pain reliever, while its mirror image has no therapeutic effect whatsoever.
Recent insights from researchers at Northwestern University and Mass General Brigham reveal that this meticulous structural control could be essential in developing a new class of nanomedicines aimed at tackling major global health challenges. Unlike current nanomedicines such as mRNA vaccines, which can vary significantly in structure, the proposed approach seeks to standardize the design of these nanomedicines to enhance their therapeutic power.
By mastering the structural aspects of these new therapies, scientists aspire to create more effective vaccines and potential cures for cancers, neurodegenerative diseases, infectious diseases, and autoimmune disorders.
The perspective detailing these findings is set for publication on April 25 in the journal Nature Reviews Bioengineering.
“Traditionally, the majority of drugs are small molecules,” remarked Northwestern’s Chad A. Mirkin, a key author of the paper. “In the realm of small molecules, it was crucial to control every atom’s placement. Any misalignment could compromise the drug’s efficacy. Now, we are advocating for a similar rigorous approach to nanomedicine. The emergence of structural nanomedicine marks a transformative opportunity in therapeutic development. By focusing on crucial structural details in our treatments, we can craft more effective and targeted therapeutic solutions.”
A leading figure in the field of nanomedicine, Mirkin serves as the George B. Rathmann Professor of multiple disciplines at Northwestern, including Chemistry and Biomedical Engineering. He co-authored the perspective with Milan Mrksich, a professor specializing in Biomedical Engineering, and Natalie Artzi, who heads the structural nanomedicine division at the Gene and Cell Therapy Institute of Mass General Brigham. Artzi is also an associate professor of medicine at Harvard and a faculty member at the Wyss Institute.
Challenges with Conventional Vaccine Design
Vaccination strategies have generally involved a “blender approach” where various components—usually an antigen derived from tumor cells and an immune-stimulating adjuvant—are amalgamated and injected into the patient.
Mirkin refers to this method as the “blender approach,” emphasizing its lack of structure. In contrast, structural nanomedicines can systematically organize these essential components. When structured at the nanoscale, these components exhibit a marked increase in effectiveness while minimizing side effects compared to their unstructured counterparts. However, the variability in nanomedicine formulations still presents challenges.
“Each batch of a nanomedicine might have diverse attributes—differences in lipid types, RNA amounts, and particle sizes,” Mirkin explained. “This variability leads to uncertainty, making it hard to ascertain whether the most effective and safe version has been produced.”
Advancing Towards Molecular Precision
To counter these issues, Mirkin, Mrksich, and Artzi propose a paradigm shift toward precise structural nanomedicines. This approach involves constructing nanomedicines using well-defined core structures that allow for careful engineering of various therapeutic elements in a specified spatial configuration. This level of control at the atomic scale opens up opportunities for integrating multiple functionalities into a single treatment, improving targeting capabilities and allowing for drug release triggered by specified cellular cues.
The perspective highlights three pioneering types of structural nanomedicines: spherical nucleic acids (SNAs), chemoflares, and megamolecules. SNAs, a type of DNA developed by Mirkin, excel at entering cells and binding to specific targets. More efficient than traditional linear DNA, these have shown promise in gene regulation, drug delivery, and even in treating aggressive skin cancers in clinical settings.
“The way we structure SNA-based vaccines can vastly influence their effectiveness,” Mirkin stated. “This could pave the way for treatments for multiple cancer types, including cures for previously untreatable cases.”
Mirkin and Artzi have further developed chemoflares, intelligent nanostructures that release chemotherapy drugs in response to specific signals from cancer cells. Megamolecules, designed by Mrksich, are engineered protein structures that can imitate antibody functions. These types of structural nanomedicines are adaptable—capable of carrying various therapeutic agents or diagnostic elements.
“Next-generation nanomedicines leverage signals from disease-specific tissues to facilitate precise and timely drug delivery,” Artzi noted. “This precision is vital for combination therapies, allowing for coordinated delivery that enhances effectiveness while minimizing systemic side effects and unintended harm.”
The Role of AI in Future Developments
Looking forward, the authors acknowledge that addressing issues of scalability, reproducibility, and the integration of multiple agents will be essential. They also emphasize the valuable role of advanced technologies such as machine learning and artificial intelligence (AI) in optimizing design and delivery.
“Analyzing structural possibilities can yield tens of thousands of arrangements for nanomedicines,” Mirkin said. “AI helps distill these vast options down to a manageable few for laboratory testing. When we take charge of structural design, we create highly effective medicines with reduced side effects. We are entering an exciting phase of structural medicine, with Northwestern in a pivotal role.”
The forthcoming article, titled “The Emerging Era of Structural Nanomedicine,” is supported by various esteemed institutions, including the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.
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