High-throughput screens identify a lipid nanoparticle that preferentially delivers mRNA to human tumors in vivo

Huayamares, Sebastian G.; Lokugamage, Melissa P.; Rab, Regina; Sanchez, Alejandro J. Da Silva; Kim, Hye-Jin; Radmand, Afsane; Loughrey, David; Lian, Liming; Hou, Yuning; Achyut, Bhagelu R.; Ehrhardt, Annette; Hong, Jeong S.; Sago, Cory D.; Paunovska, Kalina; Echeverri, Elisa Schrader; Vanover, Daryll; Santangelo, Philip J.; Sorscher, Eric J.; Dahlman, E

doi:10.1016/j.jconrel.2023.04.005

Cited by 19 publications

(7 citation statements)

References 41 publications

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“…We therefore selected a lead LNP from the (+ +) library. Specifically, we performed enrichment analysis ( 14 , 20 , 28 , 29 ), which can identify relationships between LNP structure and DNA barcode delivery ( SI Appendix , Fig. S8 A ).…”

Section: Resultsmentioning

confidence: 99%

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart

Radmand,

Kim,

Beyersdorf

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.

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Section: Resultsmentioning

confidence: 99%

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart

Radmand,

Kim,

Beyersdorf

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…For lipidic carriers, targeting a specific cell type outside the liver from a systemic administration route is a big challenge. Physicochemical engineering of LNPs, for example, with other helper lipids and PEG-lipid ratios, can alter the physical and functional in vivo distribution (“chemical targeting”) with preferential expression in lung, spleen, or tumor ( 35 , 46 – 54 ). Alternatively, “active receptor targeting” has been achieved, for example, using peptide-modified LNPs for the retina ( 55 ) or antibody-modified LNPs against CD4 ( 56 ), CD117 ( 57 ), or CD38 ( 58 ) for in vivo delivery into hematopoietic stem cells and immune cells.…”

Section: Dynamic Lipoplexes and Lnpsmentioning

confidence: 99%

“…Alternatively, “active receptor targeting” has been achieved, for example, using peptide-modified LNPs for the retina ( 55 ) or antibody-modified LNPs against CD4 ( 56 ), CD117 ( 57 ), or CD38 ( 58 ) for in vivo delivery into hematopoietic stem cells and immune cells. Chemically retargeted mRNA LNPs to nonhepatocyte cell types including endothelial cells, T cells, or tumor cells were identified by barcoded functional in vivo screening ( 52 – 54 ).…”

Section: Dynamic Lipoplexes and Lnpsmentioning

confidence: 99%

“…Some information like in vivo biodistribution and off-target effects, however, are not provided by in vitro experiments. In this respect, new high-throughput in vivo screening methods such as the barcoding system of Dahlman et al represent a more effective, economical, and ethical way compared to conventional in vivo studies ( 52 – 54 , 131 ). Translatability from small to large animals and humans is another so far unmet challenge ( 132 ).…”

Section: Future Steps and Challengesmentioning

confidence: 99%

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Dynamic carriers for therapeutic RNA delivery

Berger,

Lächelt,

Wagner

2024

Proc. Natl. Acad. Sci. U.S.A.

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Carriers for RNA delivery must be dynamic, first stabilizing and protecting therapeutic RNA during delivery to the target tissue and across cellular membrane barriers and then releasing the cargo in bioactive form. The chemical space of carriers ranges from small cationic lipids applied in lipoplexes and lipid nanoparticles, over medium-sized sequence-defined xenopeptides, to macromolecular polycations applied in polyplexes and polymer micelles. This perspective highlights the discovery of distinct virus-inspired dynamic processes that capitalize on mutual nanoparticle–host interactions to achieve potent RNA delivery. From the host side, subtle alterations of pH, ion concentration, redox potential, presence of specific proteins, receptors, or enzymes are cues, which must be recognized by the RNA nanocarrier via dynamic chemical designs including cleavable bonds, alterable physicochemical properties, and supramolecular assembly–disassembly processes to respond to changing biological microenvironment during delivery.

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“…injection. [ 126 ] However, the mechanism of such preferential transfection, and the correlation between the lipid chemical structure and the targeting efficiency are largely unknown. Also, the viability of such system toward human application needs further investigation.…”

Section: Gene Delivery Systemsmentioning

confidence: 99%

Revitalizing Cytokine‐Based Cancer Immunotherapy through Advanced Delivery Systems

Chen

Paraiso²,

Cabral

2023

Macromolecular Bioscience

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Cytokines can coordinate robust immune responses, holding great promise as therapeutics against infections, autoimmune diseases and cancers. In cancer treatment, numerous pro‐inflammatory cytokines have displayed promising efficacy in preclinical studies. However, their clinical application has been hindered by poor pharmacokinetics, significant toxicity and unsatisfactory anticancer efficacy. Thus, while IFN‐α and IL‐2 have been approved for specific cancer treatments, other cytokines still remain subject of intense investigation. To accelerate the application of cytokines as cancer immunotherapeutics, strategies need to be directed to improve their safety and anticancer performance. In this regard, delivery systems could be used to generate innovative therapies by targeting the cytokines or nucleic acids, such as DNA and mRNA, encoding the cytokines to tumor tissues. This review centers on these innovative delivery strategies for cytokines, summarizing key approaches, such as gene delivery and protein delivery, and critically examining their potential and challenges for clinical translation.This article is protected by copyright. All rights reserved

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High-throughput screens identify a lipid nanoparticle that preferentially delivers mRNA to human tumors in vivo

Cited by 19 publications

References 41 publications

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart

Dynamic carriers for therapeutic RNA delivery

Revitalizing Cytokine‐Based Cancer Immunotherapy through Advanced Delivery Systems

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