Research
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Precision gene-editing technologies, from base and prime editing to gene-sized 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 combining 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.
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 influence editing outcomes. We investigate these responses as a means to enhance the efficiency and safety of the delivery systems developed in the first thrust. At the cellular level, we employ 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 temporarily modulate the host biological environment to safely enable durable in vivo gene editing.
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 matched administration strategy. Building from our foundational work on inborn errors of metabolism in the liver, we are expanding our research to challenging extrahepatic tissues including the lungs, muscle, bone marrow, and central nervous system. To reach each tissue, we engineer customized administration strategies, from inhaled LNPs for the lungs to ligand-conjugated LNPs for systemic targeting. By co-optimizing the delivery system and administration route for the pathophysiology of each disease, we aim to develop permanent cures across a wide range of genetic disorders.
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