Research
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Precision gene-editing technologies, from base and prime editing to large gene integration, have established that nearly any mutation in the genome can, in principle, be corrected. The limiting factor is no longer what we can edit, but whether we can deliver the editors. The Jiang Lab develops non-viral delivery platforms by blending rigorous engineering with mechanistic biology to systematically overcome delivery barriers at the intracellular, cellular, and tissue scales. This multi-scale framework yields platforms that are predictable and adaptable, with the goal of equitably broadening access to curative gene-editing therapies across a broad spectrum of genetic diseases, from common conditions like cystic fibrosis and sickle cell disease to the rarest n-of-1 disorders.
Structural diversity of LNPs
loaded with prime editing mRNA
as captured by Cryo-EM.
Mechanism-driven engineering of LNPs and gene editing cargoes
We take a mechanism-driven approach to co-engineer lipid nanoparticle (LNP) delivery vehicles alongside their encapsulated gene-editing cargoes. Because prime editors, base editors, and large gene integrators are multi-component systems delivered transiently, the intracellular availability of each component (mRNA, guide RNA, and donor DNA) must be precisely coordinated in time and space for editing to succeed. We resolve this challenge along two fronts: engineering LNP formulation and morphology to control intracellular release kinetics, and tuning the sequences and structures of nucleic acid cargoes to govern their persistence, expression, and localization. Together, these efforts synchronize editor assembly at the right place and time to maximize therapeutic efficacy.
Selected representative publications:
A.Y. Jiang*, A. Cristian*, D.R. Liu et al. “Efficient prime editing in vivo and in vitro using lipid nanoparticles,” Nature Nanotechnology, In Press.
Y.A. Tao*, H.A. Sakai*, A.Y. Jiang*, N.A. Krasnow*, D.R. Liu et al. “AI-guided redesign of laboratory-evolved reverse transcriptases enhances prime editing,” Nature Biotechnology, (2026)
Understanding and modulating host responses to gene-editor delivery
The introduction of synthetic nanomaterials and foreign gene-editing machinery into living systems triggers complex host responses at both the cellular and systemic levels that fundamentally shape editing outcomes. We investigate these responses as a means to augment the efficiency and safety of the delivery systems developed in the first thrust. At the cellular level, we employ orthogonal functional genomic and pharmacological screening to map the full landscape of delivery-induced perturbations, identifying both barriers that suppress editing and opportunities for transient chemical interventions that enhance it. At the systemic level, we characterize the immunological responses elicited by LNPs and gene-editing components, using that mechanistic understanding to develop evasion and modulation strategies that ensure safety and efficacy in non-immune privileged tissues. Together, this thrust seeks to transiently engineer the host biological environment to safely enable durable in vivo gene editing.
Selected representative publications:
B. Li*, A.Y. Jiang*, I. Raji*, R. Langer, D.G. Anderson et al. “Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA,” Nature Biomedical Engineering, 9: 167-184 (2023)
In silico prediction of
prime editor peptide-HLA binding.
Gene edited cells (red) in the mouse lung airway (ciliated cells, purple; club cells, green) following inhaled delivery of LNPs.
Tissue-targeted delivery across disease contexts
Every genetic disease presents unique physiological barriers to delivery. We use the mechanistic and biological insights from our first two thrusts to adapt our modular LNP platforms to specific disease pathologies, coupling each delivery system with a tailored administration strategy. Building from our foundational work on inborn errors of metabolism in the liver, we are expanding our research to four challenging extrahepatic tissues: the lungs, muscle, bone marrow, and central nervous system. To reach each tissue, we engineer tailored administration strategies, from inhaled LNPs for the lungs to ligand-conjugated LNPs for systemic targeting. By tailoring both the delivery system and administration strategy to the pathophysiology of each disease, we aim to develop potentially permanent cures across a wide range of genetic disorders.
Selected representative publications:
A.Y. Jiang*, S. Lathwal*, R. Langer, D.G. Anderson et al. “Zwitterionic polymer-functionalized lipid nanoparticles for the nebulized delivery of mRNA,” Journal of the American Chemical Society, 146: 32567-32574 (2024)
A.Y. Jiang*, J. Witten*, I.O. Raji*, R. Langer, D.G. Anderson et al. “Combinatorial development of nebulized mRNA delivery formulations for the lungs,” Nature Nanotechnology, 19: 364-375 (2024).
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