NJIT's Xu is Developing a Timed-Release mRNA Vaccine with an Extended Shelf Life

Xiaoyang Xu, a chemical and materials engineer at NJIT who specializes in nanomedicines, has secured a $1 million award from the Gustavus and Louise Pfeiffer Research Foundation to develop the next generation of messenger RNA (mRNA) vaccines.

Xu’s immediate goal is to improve protections against COVID-19. He is designing a nano-sized delivery vehicle for gene-based medications that can be stored much longer and at higher temperatures than the current mRNA shots deployed against the virus, including by freeze-drying.

“More durable vaccines would be especially useful in rural and underdeveloped regions which lack the refrigeration capabilities, transportation technology and the capital to keep the vaccine stabilized,” he explained.

One of Xu’s core innovations is to replace the lipid casing of the current mRNA vaccines with a novel polymer he developed that can be stored at 4°C/39.2°F.  The current formulations require extreme “cold chain” storage and transportation, with temperatures as low as -20°C/-4°F to -70 °C/-94 °F, to prevent the vaccine from spoiling.

His shot is composed of millions of polymer-encapsulated mRNA nanoparticles that can release their payloads – genetic code that instructs cells to create proteins that mimic disease antigens, prompting an immune response – over time. In the case of vaccines, a controlled release – faster or slower on demand, or in stages – could potentially eliminate the need for two doses. Cancer patients would particularly benefit from the long-term controlled release of mRNA to prolong antigen production, thereby reducing the number of trips to the hospital for treatment.

In early tests, his vaccine successfully delivered the SARS-CoV-2 spike gene and generated strong spike-specific antibody titers and non-allergy-related immune responses in mice. The drugs were released over the course of eight days, peaking at two, showing the potential for controlled release. His team’s next step is to identify one or two nanoparticle formulations with superior efficacy and stability and to develop technologies to scale up the production of nanoparticles.

The nearly 80-year-old Pfeiffer Foundation, which supports university-based medical and pharmaceutical research, as well as graduate medical scholarship programs, is focused in the near-term on fighting the global pandemic. Its relationship with NJIT, however, dates back nearly two decades with instrumental investments in the university’s biomedical engineering program that helped fuel its growth. Last year, the Foundation gave NJIT $250,000 to establish an endowed scholarship fund for low-income and first-generation undergraduates majoring in biomedical engineering.

“We wish you the very best with the project, which we hope will help improve worldwide understanding of Covid-19 and its long-term effects,” the Foundation said in its award letter, noting, “The Board values the Foundation’s continuing partnership with NJIT.”

While Xu’s immediate focus is COVID-19, theoretically any protein can be expressed by changing the mRNA code in his nanoparticles. Indeed, his goal is to develop a platform with the potential to treat a multitude of diseases or different strains of the same disease.

Nucleic acid vaccines, he notes, represent an advance over live attenuated vaccines in protection from contamination in the manufacturing process and from the risk of causing disease in patients, as well as in their ease of design and speed of manufacture. However, their DNA/mRNA payload is fragile.

His nanoparticles offer heightened protection through an outer polymer layer which encapsulates smaller mRNA nanocomplexes. These structures allow him to load multiple mRNA codes into a single particle to generate different antigens, including those for SARS-CoV-2 variants.

Similarly, the ability to quickly design a flu vaccine that protects against several strains would be hugely advantageous. Drug companies must now decide months in advance which strain they think will be circulating in the coming season, as the vaccines are so difficult and time-intensive to manufacture.

“We are now testing how well these polymer nanoparticles work on SARS-CoV-2 – how much mRNA they can encapsulate, how well they penetrate cells, how well they release their payload and how effectively that translates into production of the required proteins that trigger the body’s immune system,” Xu said. “They must also be non-toxic, biocompatible (not themselves triggering an undesired chemical or immune response) and degrade naturally after they deliver their package inside the cell.”

In developing the nanoparticles, Xu’s team has tried more than 100 polymer formulations by tuning the materials used, their sizes and surface electric charges. They are studying the effects of various parameters on immune response and stability to optimize the formulations with translational potential. Meanwhile, the team is evaluating the safety of the polymers by investigating their toxicity, biocompatibility and degradation rate.

Previous polymeric formulations were limited in their capacity to deliver mRNA and DNA. Through computer-assisted design technology, Xu’s team has created a library of novel polymers that could deliver gene payloads effectively.

Xu’s nanoparticle platform is a continuation of his previous work on novel biomaterials and drug delivery systems, stemming from his work in Moderna co-founder Robert Langer’s lab at MIT, where he was a postdoctoral researcher working on obesity medicines.

In his Laboratory of Nanomedicine and Healthcare Biomaterials, he and his team are developing new technologies for medical applications in addition to controlled drug delivery mechanisms, including diagnosis, bioimaging and regenerative medicine, such as targeted nanoparticles to deliver therapies to the brain. Their aim is to develop new methods to treat cancer, obesity and cardiovascular disease, among other disorders.

In addition to their mRNA vaccine work, the team is exploring other gene-based technologies, such as CRISPR-Cas9 delivery to permanently modify diseases in which a gene is malfunctioning, and encapsulating different mRNAs for the treatment of gene disorders.