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-Catalyzed C-H activation for 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
As a Research Scientist at MIT with a background in synthetic chemist I’ve focused on rational design and synthesizing novel biodegradable ionizable lipids for efficient mRNA delivery across different organs using various administration routes. We began by designing a common precursor scaffold to synthesize both ester- and carbonate-based lipid libraries. To address congenital lung diseases like cystic fibrosis and COPD, we generated over 700 carbonate-derived lipids using a three-component reaction platform and screened them for pulmonary mRNA delivery. Following intratracheal administration, our lead lipid achieved up to 60% Cre-mediated recombination and 10% Cas9/sgRNA-driven gene editing in total lung cells of Ai9 mice—specifically targeting epithelial populations such as club and ciliated cells.3 In parallel, for liver-targeted applications, we synthesized a 384-member library of ester-derived lipids. To efficiently evaluate this large pool in vivo, we developed a high-throughput peptide barcode mRNA assay. Using this system, we identified and optimized a lead formulation that delivered mRNA to the liver with 4.5-fold greater potency than DLin-MC3-DMA, the clinical gold standard.4 To accelerate lipid discovery, we created LiON—an AI-based platform using message-passing neural networks—to predict high-performing lipids. LiON identified top candidates, including RJ-A30-T01, which outperformed MC3 and SM-102 in vivo.5 Together, these efforts establish a versatile platform for next-generation mRNA therapies aimed at treating both pulmonary and hepatic diseases.
Future research Interests:
Title: Engineering the Future of Gene Therapy: Synthetic Approaches to Non-Viral Nucleic Acid Delivery.
Messenger RNA (mRNA) vaccines have demonstrated transformative potential, particularly during the COVID-19 pandemic, where they enabled rapid, effective responses to a global health crisis. Their success—recognized by the Nobel Prize—has accelerated interest in RNA-based therapeutics beyond infectious diseases. However, first-generation mRNA vaccines present key limitations, including requirements for ultra-cold storage, high dosage, and adverse immune responses in some individuals. These challenges underscore the urgent need for next-generation delivery systems that are safer, more potent, and more accessible worldwide. My proposed research focuses on the design and synthesis of novel biodegradable ionizable lipids for the delivery of nucleic acids, including mRNA, siRNA, and plasmid DNA. These lipids will be formulated into lipid nanoparticles (LNPs) optimized for tunable biodegradability, charge, and organ-specific delivery via various administration routes. Using a combination of rational molecular design and high-throughput synthetic strategies, I will generate diverse lipid libraries that can be screened for efficacy and safety. Initial studies will be conducted in mouse models to evaluate biodistribution, transfection efficiency, immune activation, and toxicity. Promising LNP candidates will then be advanced to larger animal models in collaboration with biotechnology partners, enabling translational development of RNA-based therapies and vaccines. This interdisciplinary effort draws on my background in synthetic organic chemistry and current expertise in mRNA delivery. My goal is to bridge molecular design with functional biological outcomes—whether targeting lung epithelium for cystic fibrosis, liver cells for genetic disorders, or neural tissue for gene editing. To accelerate discovery, I will also integrate machine learning tools to guide lipid optimization and improve predictive modeling. Ultimately, this research aims to establish innovative lipid-based delivery systems for broad therapeutic applications in cancer, inflammation, neurological diseases, and pandemic preparedness—contributing to more precise, durable, and globally deployable RNA medicines.
Teaching Interests:
During my Ph.D. at North Dakota State University, I worked as a teaching assistant for several undergraduate laboratory courses, including General Chemistry, Organic Chemistry, and Advanced Organic Chemistry. My responsibilities included leading office hours, conducting weekly tutorials, delivering lectures to small groups of around fifteen students, and preparing and demonstrating organic reactions in the lab. As an educator, I am committed to helping students grasp complex concepts, foster curiosity, and develop confidence in their learning. I strive to create an engaging and supportive learning environment that encourages critical and creative thinking. Drawing from my academic and research background, I am enthusiastic about teaching a range of core courses in chemistry, medicinal chemistry, pharmaceutical sciences, chemical and biomedical engineering, drug delivery, and biomaterials. I am also open to teaching additional courses as needed by the department and contributing to curriculum development where appropriate. Throughout my career, I have mentored 14 trainees—including 8 graduate students, 4 undergraduates, 1 REU student, and 1 high school student. These experiences have shaped my approach to mentorship and inspired me to thoughtfully develop effective strategies for guiding trainees in my future lab.
References:
(1) Manan, R. S.; Zhao, P. Merging rhodium-catalysed C-H activation and hydroamination in a highly selective [4+2] imine/alkyne annulation. Nature Communications 2016, 7.
(2) Manan, R. S.; Kilaru, P.; Zhao, P. Nickel-Catalyzed Hydroimination of Alkynes. Journal of the American Chemical Society 2015, 137 (19), 6136.
(3) Li, B.*; Manan, R. S.*; Liang, S.-Q.*; Gordon, A.; Jiang, A.; Varley, A.; Gao, G.; Langer, R.; Xue, W.; Anderson, D. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nature Biotechnology 2023, 41 (10), 1410.
(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. Nature Biomedical Engineering 2023, 7 (7), 901.
(5) Witten, J.*; Raji, I.*; Manan, R. S.*; Beyer, E.; Bartlett, S.; Tang, Y.; Ebadi, M.; Lei, J.; Nguyen, D.; Oladimeji, F.et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nature Biotechnology 2024, DOI:10.1038/s41587-024-02490-y
*denotes equal contribution.