(4al) Non-Viral Delivery of Nucleic Acids for Various Therapeutic Applications

Graduate and Current Research:

Graduate Research: Late transition metal-catalyst development for alkyne coupling reactions.

Advisor: Prof. Pinjing Zhao

My thesis focuses on two major directions: 1) Rhodium-Catalysed annulation reactions towards the synthesis of 3,4-dihydroisoquinoloine by using N-H ketimines and internal alkynes.¹ 2) Nickel-Catalysed alkyne hydroimination to form 2-aza-1,3-dienes by using N-H ketimines.²

Current Research: Synthesizing Novel Ionizable Lipids for mRNA delivery to Liver and Lungs.

Advisor: Langer and Anderson Lab

My postdoctoral research at MIT focuses on synthesizing Novel biodegradable Ionizable Lipids to deliver mRNA to different organs of mice through various administration routes. I rationally designed a common precursor from which we synthesized both ester and carbonate-derived biodegradable ionizable lipids. To combat Congenital diseases such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD), I have synthesized over 700 biodegradable carbonate-derived lipids through a three-component reaction platform, and we evaluated them for pulmonary mRNA delivery. Upon Intratracheal administration of the top lipid, when encapsulated with Cre-recombinase mRNA or Cas9 mRNA/sgRNA, gene editing efficiency of up to 60% and 10% of total lung cells in Ai9 mice, respectively.³ Our nonviral RNA pulmonary delivery system is anticipated to facilitate the development of gene therapies with the potential of providing life-long health and quality-of-life benefits for patients. In another project, I synthesized Ester-derived Ionizable biodegradable Lipids to address Liver disorders, and we came up with a novel way of screening these several hundreds of lipids, i.e., peptide barcode for functional delivery of mRNA nanoparticles in vivo. To demonstrate the utility of this peptide barcode assay, we screened large libraries of lipids in a high throughput fashion. We then optimized the formulation of our lead ionizable lipid using the same peptide barcoding assay, yielding an LNP that outperforms the clinically validated lipid DLin-MC3-DMA by a factor of 4.5.⁴

Future research Interests:

Title: Non-viral delivery of Nucleic acids for various therapeutic applications.

mRNA vaccines gained worldwide recognition during the COVID-19 pandemic and recently won a Nobel Prize. To encounter any such future outbreak, we need effective treatment immediately to develop potent vaccines and strong immunity against these devastating diseases. Some disadvantages of the approved existing COVID-19 vaccines include storage at cold temperatures, severe side effects, and high doses. To overcome the drawbacks of current COVID-19 vaccines, we need more vaccines that can deliver safely and effectively. My future research directions will mainly focus on synthesizing novel biodegradable ionizable or cationic lipids and deliver nucleic acid (mRNA, siRNA, pDNA) into various organs of mice, first as a model system followed by larger animals in collaboration with biotechnology companies to develop new RNA-based therapies. My professional experiences will leverage me to bridge two fields: synthesis and mRNA delivery to develop lipid biomaterials for the next generation of mRNA-based therapies to treat cancer, inflammatory diseases, neurological disorders, gene therapy, neuro-immunotherapy, and infectious diseases.

Teaching Interests:

During my Ph.D. at North Dakota State University, I served as a teaching assistant for several undergraduate laboratory courses, such as General Chemistry, Organic Chemistry, and Advanced Organic Chemistry Laboratory. I was in charge of running office hours, providing weekly tutorials, giving a lecture to approximately fifteen students, and preparing and running the organic reactions before the class. As a teacher, I aim to strive hard to make students understand, enjoy, provide encouragement, and appreciate their learning subject. I always encourage my students to think critically and creatively. Based on my academic expertise, I am interested in teaching multiple core courses in chemistry, medicinal chemistry, pharmaceutical Sciences, chemical and Biomedical engineering, drug delivery, and biomaterials. I would also happily teach or introduce other courses per the department's requirements.

References:

1. Manan, R.S. & Zhao, P. Merging rhodium-catalysed C-H activation and hydroamination in a highly selective [4+2] imine/alkyne annulation. Nat. Comm. 7 (2016).
2. Manan, R.S., Kilaru, P. & Zhao, P. Nickel-Catalyzed Hydroimination of Alkynes. J. Amer. Chem. Soc. 137, 6136-6139 (2015).
3. Li, B. Manan, R.S., et al. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nat. Biotech. 41, 1410-1415 (2023).
4. Rhym, L.H., Manan, R.S., Koller, A., Stephanie, G. & Anderson, D.G. Peptide-encoding mRNA barcodes for the high-throughput in vivo screening of libraries of lipid nanoparticles for mRNA delivery. Nat. Biomed. Eng. 7, 901-910 (2023).