Yuan Jia

All Publications

• CRISPR-Cas9 delivery via Charge-Altering Releasable Transporters enables high-efficiency correction of CFTR Mutations with minimal transcriptomic perturbation Amaya, A. K., Jia, Y., Joo, N., Riepe, C., Warlin, N., Khasnavis, S. R., Charlesworth, C., Herrera, M., Pathak, D., Waymouth, R., Porteus, M. CELL PRESS. 2026: 1717-1718

  View details for Web of Science ID 001787054700104

• The Structure and Morphology of Single-Component Oligomeric RNA Delivery Vectors Derived from Amphiphilic Charge-Altering Releasable Transporters. ACS nano Hurst, P. J., Jia, Y., Ramsay-Burrough, S., McClellan, R. L., Arens, J. T., Khasnavis, S. R., Del Castillo, T. J., AbdElwakil, M. M., Lueckheide, M. J., Prabhu, V. M., Waymouth, R. M. 2025

  Abstract

  Advances in nucleic acid delivery have inspired efforts to mimic the function of natural viruses through the development of self-assemblies capable of gene delivery. RNA assemblies based on amphiphilic polymers are emerging as alternatives to lipid nanoparticles, but the factors that govern the self-assembly of RNA with polymeric amphiphiles are poorly understood. Here, we describe the structure of coacervate nanoparticle assemblies derived from RNA and synthetic cationic polymer amphiphiles based on Charge Altering Releasable Transporters (CARTs). CARTs are effective gene delivery agents derived from block copolymer amphiphiles. Cryogenic electron microscopy and tomography (CryoEM, CryoET), small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS) reveal that the self-assembly of RNA with low molar mass (≤10,000 g/mol) CART amphiphiles generates nanoparticles with disordered bicontinuous internal morphologies composed of interpenetrating lipid and aqueous coacervate domains. Systematic variation of the cationic and lipophilic blocks in low molar mass CART amphiphiles demonstrates that both the internal domain spacings (6 to 8 nm) and the order of the resulting bicontinuous CART-RNA assemblies depend on the CART chemical structure and the oligonucleotide cargo (mRNA vs siRNA). Notably, the presence of RNA drives the formation of bicontinuous morphologies. In contrast, CART/RNA assemblies with higher molar mass (≥28,000 g/mol) CART amphiphiles fail to generate bicontinuous assemblies, instead yielding aggregates composed of particles approximately 10 to 20 nm in diameter. This work illuminates the internal morphologies of RNA assemblies with synthetic block copolymer amphiphiles, with implications for the rational design of polymer-based RNA delivery systems.

  View details for DOI 10.1021/acsnano.5c07147

  View details for PubMedID 41194596

• In Vivo mRNA Delivery to the Lung Vascular Endothelium by Dicationic Charge-Altering Releasable Transporters. Journal of the American Chemical Society AbdElwakil, M. M., Ni, J., Ramsay-Burrough, S., Hurst, P. J., McClellan, R. L., Khasnavis, S. R., Jia, Y., Masud, S. R., Blake, T. R., Sallets, A., Haabeth, O. A., Sagiv-Barfi, I., Czerwinski, D. K., Herrera-Barrera, M., Levy, R., Wender, P. A., Kumar, M. E., Waymouth, R. M. 2025

  Abstract

  Endothelial cells (ECs) comprise the pulmonary vascular bed and play a significant role in health and diseases. Consequently, the EC niche represents an attractive therapeutic target for treating a wide range of pulmonary vascular diseases. We have identified a new class of dicationic charge-altering releasable transporters. These single-component transporters selectively deliver mRNA to the lung upon intravenous administration without the use of a targeting ligand. Significantly, the number and spatial array of cationic charges within the repeating units of the CART polymer are found to control both mRNA delivery efficacy and tissue tropism. High-resolution imaging revealed efficient mRNA delivery to endothelial cells in pulmonary arteries, veins, and capillaries. The selective lung tropism of these new CARTs, coupled with the efficient and tunable synthesis of this new family of CART amphiphiles, represents an enabling platform for research and clinical applications.

  View details for DOI 10.1021/jacs.5c06654

  View details for PubMedID 41118665

• Highly Selective O-Phenylene Bisurea Catalysts for ROP: Stabilization of Oxyanion Transition State by a Semiflexible Hydrogen Bond Pocket. Journal of the American Chemical Society Zhang, J., Lui, K. H., Zunino, R., Jia, Y., Morodo, R., Warlin, N., Hedrick, J. L., Talarico, G., Waymouth, R. M. 2024

  Abstract

  Organocatalyzed ring-opening polymerization (ROP) is a versatile technique for synthesizing biodegradable polymers, including polyesters and polycarbonates. We introduce o-phenylene bisurea (OPBU) (di)anions as a novel class of organocatalysts that are fast, easily tunable, mildly basic, and exceptionally selective. These catalysts surpass previous generations, such as thiourea, urea, and TBD, in selectivity (kp/ktr) by 8 to 120 times. OPBU catalysts facilitate the ROP of various monomers, achieving high conversions (>95%) in seconds to minutes, producing polymers with precise molecular weights and very low dispersities (Đ ≈ 1.01). This performance nearly matches the ideal distribution expected from living polymerization (Poisson distribution). Density functional theory (DFT) calculations reveal that the catalysts stabilize the oxyanion transition state via a hydrogen bond pocket similar to the "oxyanion hole" in enzymatic catalysis. Both experimental and theoretical analyses highlight the critical role of the semirigid o-phenylene linker in creating a hydrogen bond pocket that is tight yet flexible enough to accommodate the oxyanion transition state effectively. These new insights have provided a new class of organic catalysts whose accessibility, moderate basicity, excellent solubility, and unparalleled selectivity and tunability open up new opportunities for controlled polymer synthesis.

  View details for DOI 10.1021/jacs.4c04740

  View details for PubMedID 39102651

• Contrasting Roles of Counterions in Anionic Ring-Opening Polymerization Mediated by Heterocycle Organocatalysts ACS CATALYSIS Zhang, J., Lui, K., Jadrich, C. N., Jia, Y., Arrechea, P. L., Hedrick, J. L., Waymouth, R. M. 2023; 13 (24): 16097-16104

  View details for DOI 10.1021/acscatal.3c04772

  View details for Web of Science ID 001142879500001

• Flyby reaction trajectories: Chemical dynamics under extrinsic force. Science (New York, N.Y.) Liu, Y., Holm, S., Meisner, J., Jia, Y., Wu, Q., Woods, T. J., Martinez, T. J., Moore, J. S. 2021; 373 (6551): 208-212

  Abstract

  Dynamic effects are an important determinant of chemical reactivity and selectivity, but the deliberate manipulation of atomic motions during a chemical transformation is not straightforward. Here, we demonstrate that extrinsic force exerted upon cyclobutanes by stretching pendant polymer chains influences product selectivity through force-imparted nonstatistical dynamic effects on the stepwise ring-opening reaction. The high product stereoselectivity is quantified by carbon-13 labeling and shown to depend on external force, reactant stereochemistry, and intermediate stability. Computational modeling and simulations show that, besides altering energy barriers, the mechanical force activates reactive intramolecular motions nonstatistically, setting up "flyby trajectories" that advance directly to product without isomerization excursions. A mechanistic model incorporating nonstatistical dynamic effects accounts for isomer-dependent mechanochemical stereoselectivity.

  View details for DOI 10.1126/science.abi7609

  View details for PubMedID 34244412

• Architecture-Controlled Ring-Opening Polymerization for Dynamic Covalent Poly(disulfide)s JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Liu, Y., Jia, Y., Wu, Q., Moore, J. S. 2019; 141 (43): 17075–80

  Abstract

  A strategy is reported for controlling the architecture of poly(disulfide)s by ring-opening polymerization. Aryl thiol initiators shift the ring-chain equilibrium to yield cyclic polymers, while alkyl thiols favor linear ones. Control over polymerization enables synthesis of large polymers (630 kDa) and catalytic depolymerization to recycle monomers. This work provides a new avenue to create dynamic covalent polymers with controlled geometry and length, allowing better characterization of structure-property relationships to expand their materials potentials.

  View details for DOI 10.1021/jacs.9b08957

  View details for Web of Science ID 000493866300008

  View details for PubMedID 31603692