A5012356561- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Nanoparticle-Based Drug Delivery
- MicroRNA in disease regulation
- Immunotherapy and Immune Responses
- Lipid Membrane Structure and Behavior
- Organophosphorus compounds synthesis
- 3D Printing in Biomedical Research
- Virus-based gene therapy research
- Chemical synthesis and alkaloids
- CAR-T cell therapy research
- Advanced Polymer Synthesis and Characterization
- Cardiac Valve Diseases and Treatments
- Catalytic C–H Functionalization Methods
- Hydrogels: synthesis, properties, applications
- Viral Infectious Diseases and Gene Expression in Insects
- Catalytic Cross-Coupling Reactions
- Carbohydrate Chemistry and Synthesis
- Bone Tissue Engineering Materials
- Click Chemistry and Applications
- Spectroscopy Techniques in Biomedical and Chemical Research
- Spectroscopy and Chemometric Analyses
- Electrospun Nanofibers in Biomedical Applications
- Asymmetric Synthesis and Catalysis
- Protease and Inhibitor Mechanisms
University of North Carolina at Chapel Hill
2023-2025
Pharmac
2025
Massachusetts Institute of Technology
2014-2024
National University of Singapore
2021-2022
Allen Institute
2022
Koch Institute for Integrative Cancer Research At MIT
2016
Harvard–MIT Division of Health Sciences and Technology
2016
IIT@MIT
2015-2016
College of the Holy Cross
2008-2013
Skidmore College
2009
Intracellular delivery of messenger RNA (mRNA) has the potential to induce protein production for many therapeutic applications. Although lipid nanoparticles have shown considerable promise small interfering RNAs (siRNA), their utility as agents mRNA only recently been investigated. The most common siRNA formulations contain four components: an amine-containing or lipid-like material, phospholipid, cholesterol, and lipid-anchored polyethylene glycol, relative ratios which can profound...
The induction of a strong cytotoxic T cell response is an important prerequisite for successful immunotherapy against many viral diseases and tumors. Nucleotide vaccines, including mRNA vaccines with their intracellular antigen synthesis, have been shown to be potent activators immune response. delivery the cytosol presenting cells still not sufficiently well understood. Here, we report on development lipid nanoparticle formulation induce CD 8 We show transfection dendritic cells,...
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors safe and effective delivery. Synthetic nanoparticle composed poly(β-amino esters) (PBAEs) have previously demonstrated potential utility local delivery applications. To expand this to include systemic mRNA, hybrid polymer-lipid nanoformulations lungs were developed. Through coformulation PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations developed increased serum stability in vitro...
B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T-cell activation; moreover, cell misregulation is implicated in autoimmune disorders cancers such as multiple sclerosis non-Hodgkin's lymphomas. The delivery messenger RNA (mRNA) into cells can be used to modulate study these biological functions by means inducing functional protein expression a dose-dependent time-controlled manner. However, current vivo mRNA systems fail transfect...
Thousands of human diseases could be treated by selectively controlling the expression specific proteins in vivo. A new series alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable delivering mRNA with unprecedented levels vivo efficacy is demonstrated. This study highlights importance utilizing synthesis tools tandem biological inspiration to understand and improve nucleic acid delivery
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority progress in delivery has been confined to liver. Previously, we demonstrated that poly(β-amino esters), class degradable polymers, are capable systemic lungs mice when formulated into nanoparticles with poly(ethylene glycol)–lipid conjugates. Using experimental design, statistical approach optimization reduces...
Shear-thinning injectable hydrogels exploit dynamic noncovalent cross-links to flow upon applied stress and rapidly self-heal once the is relaxed. These materials continue gather interest as they afford minimally invasive deployment in body for a variety of biomedical applications. Here, we present rationally engineered polymer–nanoparticle (PNP) interactions based on electrostatic forces fabrication self-assembled with shear-thinning self-healing properties. The selective adsorption...
Abstract RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies deliver remains important for realizing full clinical potential. Here, we develop lipid nanoparticle formulations that can short interfering (for gene silencing) or messenger upregulation). Specifically, study how tail length, geometry, linker spacing in diketopiperazine materials influences LNP potency with siRNAs mRNAs....
In calcific aortic valve disease (CAVD), microcalcifications originating from nanoscale calcifying vesicles disrupt the (AV) leaflets, which consist of three (biomechanically) distinct layers: fibrosa, spongiosa, and ventricularis. CAVD has no pharmacotherapy lacks in vitro models as a result complex valvular biomechanical features surrounding resident mechanosensitive interstitial cells (VICs). We measured layer-specific mechanical properties human AV engineered three-dimensional...
The ability to engineer immune function has transformed modern medicine, highlighted by the success of vaccinations and recent efforts in cancer immunotherapy. Further directions programming system focus on design immunomodulatory biomaterials that can recruit, engage with, program cells locally vivo. Here, we synthesized shear-thinning self-healing polymer–nanoparticle (PNP) hydrogels as a tunable injectable biomaterial platform for local dendritic cell (DC) recruitment. PNP gels were...
Despite tremendous interest in gene therapies, the systemic delivery of nucleic acids still faces substantial challenges. To successfully administer acids, one approach is to encapsulate them lipid nanoparticles (LNPs). However, LNPs administered intravenously substantially accumulate liver where they are taken up by reticuloendothelial system (RES). Here, we prior a liposome designed transiently occupy cells, Nanoprimer. This study demonstrates that pretreatment mice with Nanoprimer...
Abstract Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many AD‐risk loci identified in genome wide association studies and present promising target for anti‐inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations examined, lead candidate that supports efficient delivery cultures human stem cell‐derived microglia‐like...
Hypoxia is a common hallmark of human disease that characterized by abnormally low oxygen levels in the body. While effects hypoxia on many small molecule-based drugs are known, its several classes next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy- and mechanism-driven study details how impacts cellular response to mRNA delivered using 4 different chemistries lipid nanoparticles (LNPs, frontrunner class drug delivery vehicles...
A central goal of chemical and drug delivery sciences is to maximize the therapeutic efficacy a given at lowest possible dose. Here, we report generalizable strategy that can be utilized improve mRNA drugs using lipid nanoparticles (LNPs), clinically approved chemistry platforms in Moderna Pfizer/BioNTech COVID-19 vaccines. In brief, our updates LNPs incorporate adenosine triphosphate (ATP) alongside mRNA, modification results upward 79-fold increase LNP-delivered mRNA-encoded protein...
A versatile strategy for C7-selective boronation of tryptophans, tryptamines, and 3-alkylindoles by way a single-pot C2/C7-diboronation-C2-protodeboronation sequence is described. The combination mild iridium-catalyzed C2/C7-diboronation followed an in situ palladium-catalyzed C2-protodeboronation allows efficient entry to valuable C7-boroindoles that enable further C7-derivatization. versatility the chemistry highlighted gram-scale synthesis C7-boronated N-Boc-L-tryptophan methyl ester...
Abstract The production of new proteins with messenger RNA (mRNA) has gained a broad interest due to its potential for addressing wide range diseases. Here, the design and characterization novel ionizable poly(β‐amino ester)‐ co ‐poly(caprolactone) terpolymers, synthesized via combination ring opening polymerization Michael step‐growth polymerization, are reported. versatility this method is demonstrated by varying number caprolactone units attached each ester) (PBAE) terpolymer. ability...
In calcific aortic valve disease (CAVD), mechanosensitive valvular cells respond to fibrosis- and calcification-induced tissue stiffening, further driving pathophysiology. No pharmacotherapeutics are available treat CAVD because of the paucity (i) appropriate experimental models that recapitulate this complex environment (ii) benchmarking novel engineered (AV)–model performance. We established a biomaterial-based model mimicking biomechanics human AV disease-prone fibrosa layer,...
The concise, enantioselective total syntheses of (+)-asperazine (1), (+)-iso-pestalazine A (2), and (+)-pestalazine (3) have been achieved by the development a late-stage C3-C8' Friedel-Crafts union polycyclic diketopiperazines. Our modular strategy enables complex diketopiperazines in virtually their final forms, thus providing rapid highly convergent assembly at challenging quaternary stereocenter these dimeric alkaloids. significance this carbon-carbon bond formation can be gauged...
Abstract Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors safe and effective delivery. Synthetic nanoparticle composed poly(β‐amino esters) (PBAEs) have previously demonstrated potential utility local delivery applications. To expand this to include systemic mRNA, hybrid polymer–lipid nanoformulations lungs were developed. Through coformulation PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations developed increased serum stability in...
Abstract Even though lipid nanoparticles (LNPs) can deliver messenger RNA (mRNA) payloads into cells, their efficiency is often limited by endosomal trapping which prevents from acting therapeutically. Improving the percentage of LNPs that escape endosomes and enter cytoplasm therefore an area active research interest could lead to improved safety profiles reduced manufacturing costs mRNA drugs. Here, tannic acid [TA(+) LNPs] are reported as effective delivery platform for payloads. The...