A5072617906- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- CAR-T cell therapy research
- MicroRNA in disease regulation
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- Nanopore and Nanochannel Transport Studies
- Bacteriophages and microbial interactions
- Nanowire Synthesis and Applications
- RNA Research and Splicing
- Nanoparticle-Based Drug Delivery
- Hepatitis B Virus Studies
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Cancer Cells and Metastasis
- Hepatitis Viruses Studies and Epidemiology
- Immune cells in cancer
- Phagocytosis and Immune Regulation
- SARS-CoV-2 and COVID-19 Research
- Congenital heart defects research
- Advanced Drug Delivery Systems
- Extracellular vesicles in disease
- Nanoplatforms for cancer theranostics
- Viral Infectious Diseases and Gene Expression in Insects
University of Pennsylvania
2019-2025
California University of Pennsylvania
2020
Philadelphia University
2020
A major challenge to advance lipid nanoparticles (LNPs) for RNA therapeutics is the development of formulations that can be produced reliably across various scales drug development. Microfluidics generate LNPs with precisely defined properties, but have been limited by challenges in scaling throughput. To address this challenge, we present a scalable, parallelized microfluidic device (PMD) incorporates an array 128 mixing channels operate simultaneously. The PMD achieves >100× production...
Nucleic acids, such as messenger RNAs, antisense oligonucleotides, and short interfering hold great promise for treating previously 'undruggable' diseases. However, there are numerous biological barriers that hinder nucleic acid delivery to target cells tissues. While lipid nanoparticles (LNPs) have been developed protect acids from degradation mediate their intracellular delivery, it is challenging predict how alterations in LNP formulation parameters influence different organs. In this...
Abstract Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted of therapeutics activated liver-resident fibroblasts for fibrosis treatment remains challenging. Here, we develop a combinatorial library anisamide ligand-tethered lipidoids (AA-lipidoids) using one-pot, two-step modular synthetic method and adopt two-round screening strategy identify AA-lipidoids with both high potency selectivity deliver payloads fibroblasts. The lead...
Abstract With six therapies approved by the Food and Drug Association, chimeric antigen receptor (CAR) T cells have reshaped cancer immunotherapy. However, these rely on ex vivo viral transduction to induce permanent CAR expression in cells, which contributes high production costs long‐term side effects. Thus, this work aims develop an cell engineering platform streamline while using mRNA transient, tunable expression. Specifically, ionizable lipid nanoparticle (LNP) is utilized as platforms...
Lipid nanoparticles (LNPs) are a potent delivery technology that have made it possible for the recent clinical breakthroughs in mRNA therapeutics and vaccines. A key challenge to broader implementation of vaccines is development produce precisely defined LNP formulations, with throughput can scale from discovery commercial manufacturing meet stringent standards pharmaceutical industry. To address these challenges, we developed microfluidic chip incorporates 1×, 10×, or 256× LNP-generating...
Abstract Lipid nanoparticles for delivering mRNA therapeutics hold immense promise the treatment of a wide range lung-associated diseases. However, lack effective methodologies capable identifying pulmonary delivery profile chemically distinct lipid libraries poses significant obstacle to advancement therapeutics. Here we report implementation barcoded high-throughput screening system as means identify lung-targeting efficacy cationic, degradable lipid-like materials. We combinatorially...
Abstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious via linkers boosts mRNA delivery efficiency up three orders magnitude. Combinatorial...
Evasion of apoptosis is a hallmark cancer, attributed in part to overexpression the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). In variety cancer types, including lymphoma, Bcl-2 overexpressed. Therapeutic targeting has demonstrated efficacy clinic and subject extensive clinical testing combination with chemotherapy. Therefore, development co-delivery systems for agents, such as small interfering RNA (siRNA), chemotherapeutics, doxorubicin (DOX), holds promise enabling therapies. Lipid...
Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with survival rate of 3 to 6 mo for those advanced disease despite great efforts develop effective therapies. Thus, there is an urgent clinical need innovative and more MM therapeutics. Insights suggest endothelial cells within marrow microenvironment play critical role. Specifically, cyclophilin A (CyPA), homing factor secreted by (BMECs), homing, progression, survival,...
Lipid nanoparticles (LNPs) have emerged as a viable, clinically-validated platform for the delivery of mRNA therapeutics. LNPs been utilized systems applications including vaccines, gene therapy, and cancer immunotherapy. However, LNPs, which are typically composed ionizable lipids, cholesterol, helper lipid-anchored polyethylene glycol, often traffic to liver limits therapeutic potential platform. Several approaches proposed resolve this tropism such post-synthesis surface modification or...
Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing immune evasion immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin promote macrophage (Mφ)...
Immune modulation through the intracellular delivery of nucleoside-modified mRNA to immune cells is an attractive approach for in vivo immunoengineering, with applications infectious disease, cancer immunotherapy, and beyond. Lipid nanoparticles (LNPs) have come fore as a promising nucleic acid platform, but LNP design criteria remain poorly defined, making rate-limiting step discovery screening process. In this study, we employed high-throughput based on molecular barcoding investigate...
In the past 10 years, CRISPR-Cas9 has revolutionized gene-editing field due to its modularity, simplicity, and efficacy. It been applied for creation of in vivo models, further understand human biology, toward curing genetic diseases. However, there remain significant delivery barriers application clinic, especially extrahepatic applications. this work, high-throughput molecular barcoding techniques were used alongside traditional screening methodologies simultaneously evaluate LNP...
Lipid nanoparticles (LNPs) have attracted widespread attention recently with the successful development of COVID-19 mRNA vaccines by Moderna and Pfizer/BioNTech. These demonstrated efficacy mRNA-LNP therapeutics opened door for future clinical applications. In systems, LNPs serve as delivery platforms that protect cargo from degradation nucleases mediate their intracellular delivery. The are typically composed four components: an ionizable lipid, a phospholipid, cholesterol, lipid-anchored...
Abstract Oral administration of nucleic acids, such as small interfering RNAs and antisense oligonucleotides, represents a potent modality for treating many gastrointestinal (GI) diseases. However, their use is limited due to lack carriers that can effectively mediate delivery through GI barriers, including gastric enzymes mucus membranes. Lipid nanoparticles (LNPs) are an emerging system protect acids from degradation intracellular delivery, but few studies have evaluated ability overcome...