Tuning the organ-selectivity of mRNA expression through dendrimer-based lipid nanoparticles

Speaker(s)
Fan Zhang, Ph.D.
Sponsor(s)
NCI DCP Early Career Scientist Spotlight Research Seminar Series
Major Program
Supportive Care and Symptom Management
Research Group
Breast and Gynecologic Cancer

Date Posted

Speaker

Fan Zhang, Ph.D.

Fan Zhang, Ph.D.
Assistant Professor
Department of Pharmaceutics
University of Florida

Fan Zhang, Ph.D. received his Ph.D. from Johns Hopkins University in Materials Science & Engineering. His graduate work established the guiding principles for designing nanomedicines to target neuroinflammation. To expand the clinical impact of his research, he then undertook postdoctoral training at the clinical research division of Fred Hutchinson Cancer Research Center. This experience solidified his foundation in immuno-oncology, cell & gene therapy, and experimental tumor models. Dr. Zhang’s research focuses on developing synthetic nanoplatforms to direct immune cells as ‘living therapeutics’. To this end, his laboratory integrates materials science, immunology, synthetic biology, and translational medicine to create novel nanotherapeutics for controlled modulation of the immune system. The overarching goal of his research is to establish a fundamental understanding of nanotherapeutic design and the ways it interacts with the immune system. The ultimate goal of his research is to translate nanomedicine to the clinic.

Abstract:
The predominant liver-targeting of lipid nanoparticles (LNPs) significantly limited the general application of IVT-mRNA as a systemic therapy. To identify novel LNPs that deliver mRNA beyond the liver, we constructed a library of ionizable lipids using dendrimer as a scaffold. Through a combination of in vitro and in vivo screening, we discovered that the structure of internal amines (i.e., secondary, tertiary, or quaternary amines) within the ionizable lipids determines the selectivity of mRNA expression in either spleen, liver, or lung; The apparent pKa of the DLNPs further influence the amount of expression in these organs. Guided by this mechanism, we designed 9 patentable lead mRNA formulations with superior in vivo transfection than FDA-approved LNPs. This discovery provides guiding principles for rationally designing LNP for spleen targeting. Implemented in clinics, this delivery platforms can be used for targeted delivery of RNAs to spleens as prophylactic or therapeutic vaccines for immune-related disorders.


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