Dong et al. encoded the ICD-inducing protein 4HB in LNPs optimized for tumor cell specificity and hepatocyte avoidance, which significantly improved tumor cargo expression compared to a clinical control LNP (>90% vs. ~25%). mRNA engineering via inclusion of UTRs complementary to non-tumor miRNAs (suppressive for liver) reduced off-target cargo distribution, markers of tissue injury, and body weight loss, without compromising tumor expression. The platform synergized with ICB in diverse “cold” tumor models via i.t. and i.v. routes, without systemic toxicity, enhancing infiltration of diverse immune cell types, including CD8+ T cells and macrophages.
Contributed by Morgan Janes
ABSTRACT: Messenger RNA (mRNA) therapeutics hold great promise for oncology but their efficacy is limited by systemic off-target effects and immunosuppressive tumour microenvironments. Here we present TITUR, a tumour-customizable mRNA nanomedicine platform that integrates tumour-customizable ionizable lipids (TIs) and tumour-specific untranslated regions (TURs) to enhance tumour-selective mRNA delivery and expression. This dual-engineered approach enables the precise intratumoural expression of 4HB, an immunogenic cell death-inducing protein, while mitigating systemic toxicities. Using murine models of immunologically cold tumours, including melanoma and triple-negative breast cancer, TITUR-mediated 4HB delivery induced tumour-specific immunogenic cell death, remodelled the tumour microenvironment and enhanced immune cell infiltration. When combined with immune checkpoint inhibitors, 4HB TITUR suppressed primary and metastatic tumour growth, while also exhibiting vaccine-like properties by reducing tumour recurrence and eliciting systemic antitumour immunity. Furthermore, it demonstrated a superior safety profile compared with conventional mRNA delivery methods. Our data indicate that TITUR may serve as a versatile approach to address the limitations of current immunotherapies and support the development of personalized mRNA nanomedicines.
Author Info: (1) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (2) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (3) Leslie
Author Info: (1) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (2) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (3) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (4) Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. (5) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (6) Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. (7) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (8) Department of Chemistry, University of Toronto, Toronto, Ontario, Canada. (9) Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. (10) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (11) Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. (12) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (13) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (14) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. (15) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (16) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (17) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (18) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. bw.li@utoronto.ca. Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. bw.li@utoronto.ca. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada. bw.li@utoronto.ca. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. bw.li@utoronto.ca.
