TORONTO – Messenger RNA (mRNA) therapeutics hold significant promise for the future of personalized cancer treatment, but persistent off-target effects and treatment-resistant tumour microenvironments have limited progress.
A new study from researchers at the University of Toronto and Princess Margaret Cancer Centre, University Health Network, presents a tumour-customizable mRNA nanomedicine platform that demonstrated efficient mRNA delivery to cancer cells in animal models of melanoma and triple-negative breast cancer while minimizing harmful effects in healthy tissues.
The research team also showed how their system elicited a strong immune response, effectively turning "cold" tumours that do not respond well to immunotherapy into "hot" tumours that do.
The preclinical study, led by Bowen Li, assistant professor, Leslie Dan Faculty of Pharmacy, University of Toronto, was published today in Nature Nanotechnology.
"We need to address off-target effects if we want to realize the therapeutic potential of mRNA for cancer," said Li, who also holds the Canada Research Chair in RNA and Therapeutics, and GSK Chair in Pharmaceutics and Drug Delivery. "This study shows that with the new platform, we can quickly customize a delivery system for a specific cancer type while also reducing off-target toxicity."
The platform, called TITUR, integrates two key components: tumour-customized ionizable lipids (TIs) that deliver the mRNA specifically to tumour cells, and tumour-specific untranslated regions (TURs) that restrict mRNA translation of the chosen therapeutic protein exclusively to tumour cells. This dual-engineered approach enables the expression of 4HB, an immunogenic cell death (ICD)-inducing protein, precisely in tumour cells while mitigating systemic toxicities.
"The 4HB protein induces immunogenic cell death, which is desirable because this process not only kills tumour cells but also activates the immune system, helping eliminate residual cancer cells. But 4HB can also be highly toxic to healthy cells," said Li. By limiting 4HB expression almost exclusively to tumour cells, the TITUR platform reduced tumour growth while exhibiting a superior safety profile compared to industry-standard approaches that rely on mRNA delivery systems used for vaccines against infectious diseases like COVID-19.
"The TITUR platform brings personalized medicine for cancer closer to reality," said Hansen He, senior scientist at the Princess Margaret Cancer Centre. "In the future, if we can integrate sequencing data from patient samples to further refine the TITUR design, it could enable truly personalized cancer immunotherapy with improved safety and efficacy."
A versatile, modular solution to key challenges in mRNA cancer treatment, the new study shows TITUR provides highly specific and effective therapies while inducing a durable immune response that may reduce the risk of recurrence and metastasis. Both components of the platform can be customized based on the tumour type and therapeutic needs, and future research will aim to expand the platform for more cancer types.
This work was supported by the Princess Margaret Cancer Foundation's Invest in Research program and RNA Medicine Initiative operating fund, and the Natural Sciences and Engineering Research Council of Canada (NSERC).
