Purdue Researchers Develop Freeze-Dried mRNA Delivery System for Cancer Therapy
核心洞察
Purdue University researchers have developed LENN, a virus-mimicking nanoparticle system that can deliver mRNA therapies to bladder cancer cells while maintaining stability after freeze-drying and storage.
The LENN system addresses major storage challenges of current lipid nanoparticle delivery systems, which require continuous storage below minus 45 degrees Celsius, by enabling powder storage at minus 20 degrees Celsius.
Research published in PNAS demonstrates that LENN targets cancer cells through natural pathways without triggering immune responses, potentially enabling effective redosing unlike current viral vectors.
Researchers at Purdue University have developed a breakthrough mRNA delivery system that could revolutionize cancer therapy by solving critical storage and targeting challenges that have limited current approaches. The layer-by-layer elastin-like polypeptide nucleic acid nanoparticle (LENN) system demonstrates the ability to deliver mRNA therapies to bladder cancer cells while maintaining full biological activity after freeze-drying and storage.
The research, published in the Proceedings of the National Academy of Sciences, was led by David Thompson, professor in the James Tarpo Jr. and Margaret Tarpo Department of Chemistry and member of the Purdue Institute for Cancer Research and the Purdue Institute for Drug Discovery. Saloni Darji, a commercialization postdoctoral research associate, served as the paper's lead author.
Addressing Storage Limitations
The LENN system tackles a major obstacle facing current mRNA delivery technologies. "We have validated that the LENN system can be freeze-dried and stored for several days as a powder and retain full biological activity after rehydration," Thompson explained. This represents a significant advancement over lipid nanoparticle delivery systems, which must be continuously stored as liquids below minus 45 degrees Celsius to maintain their activity.
The stability testing involved concentrating LENN formulations, freezing them at minus 20 degrees Celsius, cooling to minus 80 degrees Celsius, and lyophilizing overnight. The lyophilized powders were stored at minus 20 degrees Celsius for three days before rehydration and testing for structural integrity and encapsulation efficiency compared to fresh samples.
Virus-Mimicking Design
LENN particles mimic the multilayer structure of viruses to deliver nucleic acid-based therapies to targeted cells. The system comprises two protective layers: an inner shell that condenses the therapies and an outer shell that protects against degradation and immune system evasion.
"LENN can target the mRNA to a specific cell type based on that cell's surface information," Darji said. "In the case of bladder cancer cells, LENN targets a specific cell surface receptor already present on the tumor cell. The LENN system targets it and enters through the natural pathway."
Immune Response Advantages
A critical finding emerged from collaboration with Christina Ferreira, assistant research professor at Bindley Bioscience Center, who conducted multiple reaction monitoring (MRM) profiling tests. "MRM profiling showed that LENN doesn't alter the natural pathway of entry nor does it trigger any signs of an immune response, which would be a concern of long-term viability for this technology," Thompson noted.
This characteristic distinguishes LENN from current viral vectors, which trigger immune responses that make redosing ineffective because the immune system clears subsequent doses. Thompson confirmed that "this biomanufacturable system homes to the target tissue and neither alters the natural entry pathway to those tumors nor triggers an immune response. LENN traffics to the cancer cells then releases the mRNA within the cells, leading to expression of the protein encoded by the mRNA."
Manufacturing and Commercialization
The LENN system offers additional advantages in manufacturing, as its components are products of biological expression that enable a readily manufacturable delivery system. Thompson has disclosed LENN to the Purdue Innovates Office of Technology Commercialization, which has applied for a patent to protect the intellectual property.
The study highlights compelling features of the therapy-delivering system with respect to size, targetability, encapsulation efficiency, complex stability, gene expression and "green" manufacturability, positioning it as a promising platform for mRNA therapeutic applications requiring long-term storage.
Future Development
Thompson indicated that next phases will focus on upscaling the system to support further preclinical evaluation, including efficacy and safety studies in mouse models of bladder cancer in collaboration with Bennett Elzey in the Department of Comparative Pathobiology and the Purdue Institute for Cancer Research. This work represents part of Purdue's One Health initiative, which brings together research on human, animal and plant health.