Research focuses in the Drug Discovery and Delivery Laboratory:
Cell-specific and multifunctional drug delivery in vivo has been regarded as one of the most challenging issues in the field of drug delivery. A wide variety of cell types in humans still cannot be efficiently and specifically reached by delivery systems such as neurons, lung epithelial cells, metastatic tumor cells, and immune cells. An even more formidable task is delivering multiple payloads into specific cells and tissues. To address these challenges, my laboratory-Drug Discovery and Delivery Laboratory focuses on the following research areas: 1) to develop cell specific drug delivery systems; 2) to construct multifunctional drug delivery systems; 3) to demonstrate therapeutic efficacy of these systems for treating genetic disorders, infectious diseases, as well as cancer.
Platform biotechnologies under development in the Drug Discovery and Delivery Laboratory:
- Developing new biomaterials such as lipid nanoparticles for therapeutic and diagnostic applications
- Engineering RNA molecules including mRNAs, oligonucleotides, and the CRISPR systems
- Constructing adoptive cell therapy such as macrophages, dendritic cells, and stem cells
LIPID NANOPARTICLES
Effective and safe delivery of RNA-based therapeutics is a key challenge in clinical applications. We have designed and developed innovative lipid nanoparticles (LNPs) for RNA delivery to diverse organs, including the liver, spleen, tumors, brain, and wound sites. For example, TT3 LNPs effectively restored human factor IX (hFIX) levels in knockout mice by delivering hFIX mRNA to the liver. ROS-responsive trisulfide-derived LNPs (TS LNPs) were designed to reduce reactive oxygen species at wound sites and deliver IL4 mRNA, modulating inflammation and accelerating diabetic wound healing with a single administration. Additionally, BBB-crossing lipid nanoparticles (BLNPs), such as MK16 BLNPs, successfully delivered Pten mRNA in glioma models, achieving a ~70% complete response rate. These innovative LNPs exhibit significantly higher RNA delivery efficiency than FDA-approved LNPs and hold potential for diverse clinical applications. Several of these LNP platforms have been licensed and are undergoing clinical trials or development as clinical candidates for transformative RNA-based therapies.
RNA ENGINEERING
RNA-based therapeutics represent a groundbreaking class of drugs. We have developed a variety of RNAs, including CRISPR-RNAs (crRNAs), mRNAs, and oligonucleotide, optimized for gene editing and therapeutic applications. Notably, Acidaminococcus sp. Cpf1 (AsCpf1) exhibited enhanced editing efficiency when combining engineered crRNAs and AsCpf1 mRNAs, achieving over 300% improvement compared to unmodified counterparts. We also identified potent Cpf1 inhibitors using phosphorothioate (PS)-modified DNA oligonucleotides, demonstrating time- and dose-dependent activity. To boost mRNA translation, we developed NASAR UTRs through a de novo design process, achieving ten-fold higher efficiency compared to endogenous UTRs. NASAR mRNAs delivered via LNPs induced strong SARS-CoV-2 antigen-specific immune responses in mice. To overcome challenges in CNS delivery, we created a BBB-crossing conjugate (BCC) system utilizing γ-secretase-mediated transcytosis. BCC10-oligonucleotide conjugates enabled effective brain delivery, achieving gene silencing in wild-type mice, human tissues, and ALS models. These innovations have been licensed as clinical candidates to advance RNA therapeutics.
CELL THERAPY
Cell therapy has revolutionized the treatment of diseases like blood cancers and offers potential for broader applications. We developed macrophages (MACs) loaded with antimicrobial peptides linked to cathepsin B in lysosomes using vitamin C lipid nanoparticles to deliver mRNA. Adoptive MAC transfer eliminated multidrug-resistant (MDR) bacteria, including S. aureus and E. coli, and restored immunocompromised septic mice, demonstrating a novel approach to combat MDR bacteria-induced sepsis and expand nanoparticle-enabled cell therapies to infections and cancers. Adipose stem cells (ASCs) are promising for tissue regeneration but face limitations in repair capability. To enhance therapeutic outcomes, we designed isomannide-derived lipid nanoparticles (DIM1T LNPs) for RNA delivery, enabling durable protein production in ASCs. DIM1T LNPs co-delivered self-amplifying RNA (saRNA) and E3 mRNA (SEC complex) to engineer ASCs with extended secretion of hepatocyte growth factor (HGF) and CXCL12, significantly improving diabetic wound healing. These advances highlight the potential of LNPs to enhance and empower cell therapies.