Chimeric Antigen Cytotoxic Receptors for In Vivo Engineering of Tumor-Targeting NK Cells DOI Creative Commons
Neha Diwanji, Daniel R. Getts, Yuxiao Wang

et al.

ImmunoHorizons, Journal Year: 2024, Volume and Issue: 8(1), P. 97 - 105

Published: Jan. 1, 2024

Abstract Chimeric Ag receptor (CAR) NK cells are challenging to manufacture and fail achieve consistent tumor infiltration sustained cytolytic function in the microenvironment. In vivo engineering of using mRNA-based CAR delivery may overcome these issues. this study, we developed an programming method by designing CARs that leverage biology cell receptors for type–specific expression function. These were engineered fusion a recognition domain with natural cytotoxic family including NKp30, NKp44, NKp46. Our results demonstrated receptor–based can engage endogenous signaling adaptors effectively activate human lysis cytokine production. Specifically, discovered stable NKp44-based was contingent on presence immune cell–specific adaptor DAP12. This innovative strategy facilitates direct situ cells, enhancing safety minimizing off-target effects nontargeted, healthy tissues.

Language: Английский

Delivery of nucleic acid based genome editing platforms via lipid nanoparticles: Clinical applications DOI

Razan Masarwy,

Lior Stotsky‐Oterin,

Aviad Elisha

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 211, P. 115359 - 115359

Published: June 12, 2024

Language: Английский

Citations

16
Ionizable Lipids with Optimized Linkers Enable Lung-Specific, Lipid Nanoparticle-Mediated mRNA Delivery for Treatment of Metastatic Lung Tumors DOI Creative Commons
Gonna Somu Naidu, Riccardo Rampado, Preeti Sharma

et al.

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery system for vaccines and therapeutic mRNAs. Ionizable lipids are the most pivotal component of LNPs due to their ability electrostatically interact with mRNA, allowing its encapsulation while concurrently enabling endosomal escape following cellular internalization. Thus, extensive research has been performed optimize ionizable lipid structure develop formulations that well tolerated allow efficient targeting different organs result in high sustained mRNA expression. However, one facet lipids' mostly overlooked: linker segment between headgroup tails. Here, we screened rationally designed library biodegradable linkers. We extensively characterized formulated using these elucidated how minor structural changes radically influenced LNPs' biodistribution vivo. showed use amide urea linkers can modulate pKa, resulting an improved specificity lung transfection. Finally, demonstrated (lipid 35) form entrapping bacterial toxin [pseudomonas exotoxin A (mmPE)] reduced tumor burden significantly increased survival mice metastasis.

Language: Английский

Citations

4
A lipid nanoparticle platform incorporating trehalose glycolipid for exceptional mRNA vaccine safety DOI Creative Commons
Seo‐Hyeon Bae, Soyeon Yoo, Ji Sun Lee

et al.

Bioactive Materials, Journal Year: 2024, Volume and Issue: 38, P. 486 - 498

Published: May 14, 2024

The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control the COVID-19 pandemic. However, mRNA have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, pericarditis. In this study, we investigated trehalose glycolipids-containing LNP (LNP S050L) reduce risks associated ionizable lipids. Trehalose glycolipids can form hydrogen bonds polar biomolecules, allowing formation a stable structure by replacing half efficacy safety S050L were evaluated encapsulating encoding luciferase reporter gene measuring expression organ toxicity, respectively. Furthermore, mice immunized an S050L-formulated vaccine expressing influenza hemagglutinin exhibited significant reduction in heart, spleen, liver, while sustaining immune efficiency, compared conventional LNPs (Con-LNPs). Our findings suggest that S050L, glycolipid-based LNP, could facilitate safe improved safety.

Language: Английский

Citations

14
Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo DOI Creative Commons
Tian Zhang,

Han Yin,

Li Yu

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(6), P. 109804 - 109804

Published: April 23, 2024

Nucleic acid therapeutics offer tremendous promise for addressing a wide range of common public health conditions. However, the

Language: Английский

Citations

13
Lipid nanoparticle (LNP) mediated mRNA delivery in cardiovascular diseases: Advances in genome editing and CAR T cell therapy DOI

Setareh Soroudi,

Mahmoud Reza Jaafari,

Leila Arabi

et al.

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 372, P. 113 - 140

Published: June 15, 2024

Language: Английский

Citations

10
Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery DOI Open Access
Pei Huang, Hongzhang Deng,

Changrong Wang

et al.

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(13)

Published: Nov. 6, 2023

Abstract Messenger RNA (mRNA)‐based therapy has emerged as a powerful, safe, and rapidly scalable therapeutic approach that involves technologies for both mRNA itself the delivery vehicle. Although there are some unique challenges different applications of therapy, common challenge all therapeutics is transport into target cell cytoplasm sufficient protein expression. This review focused on behaviors at cellular level nanotechnology‐mediated systems, which have not been comprehensively reviewed yet. First, four main introduced, including immunotherapy, replacement genome editing, reprogramming. Second, types cargos systems summarized. Third, strategies to enhance efficiency during trafficking process highlighted, accumulation cell, internalization endosomal escape, release from nanocarrier, translation protein. Finally, opportunities development presented. can provide new insights future fabrication nanocarriers with desirable performance.

Language: Английский

Citations

17
Cationic Lipid Pairs Enhance Liver-to-Lung Tropism of Lipid Nanoparticles for In Vivo mRNA Delivery DOI

Gege Zeng,

Zepeng He, Haihong Yang

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(20), P. 25698 - 25709

Published: May 8, 2024

Much of current clinical interest has focused on mRNA therapeutics for the treatment lung-associated diseases, such as infections, genetic disorders, and cancers. However, safe efficient delivery to lungs, especially different pulmonary cell types, is still a formidable challenge. In this paper, we proposed cationic lipid pair (CLP) strategy, which utilized liver-targeted ionizable its derived quaternary ammonium CLP improve liver-to-lung tropism four-component nanoparticles (LNPs) in vivo delivery. Interestingly, structure–activity investigation identified that using lipids with higher performance their counterparts optimal design improving lung-targeted The strategy was also verified be universal suitable clinically available SM-102 ALC-0315 develop LNP systems. Moreover, demonstrated CLP-based LNPs were exhibited potent transfection endothelial epithelial cells. As result, provided powerful shifting preference from liver exhibiting great potential broadening application scenario mRNA-based therapy.

Language: Английский

Citations

8
Effect of Lipid Nanoparticle Physico-Chemical Properties and Composition on Their Interaction with the Immune System DOI Creative Commons
Laura Catenacci,

Rachele Rossi,

Francesca Sechi

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(12), P. 1521 - 1521

Published: Nov. 26, 2024

Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune plays critical role in the response to these nanocarriers, with innate cells initiating an early adaptive mediating more specific reaction, sometimes leading potential adverse effects. Recent studies that LNPs is mediated by Toll-like receptors (TLRs) other pattern recognition (PRRs), which recognize lipid components of nanoparticles. This can trigger activation inflammatory pathways production cytokines chemokines, effects such fever, inflammation, pain at injection site. On hand, appears be primarily directed against protein encoded cargo, little evidence ongoing LNP itself. Understanding relationship between development safe effective systems. In fact, targeting essential develop vaccines, well therapies cancer or infections. There lack research literature has systematically studied factors influence interaction further needed better elucidate mechanisms underlying LNPs. this review, we discuss LNPs’ composition, physico-chemical properties, size, shape, surface charge, corona formation affect reactivity system, thus providing guide on new formulations could gain favorable efficacy/safety profile.

Language: Английский

Citations

8
Oxidized mRNA Lipid Nanoparticles for In Situ Chimeric Antigen Receptor Monocyte Engineering DOI Creative Commons

Alvin J. Mukalel,

Alex G. Hamilton, Margaret M. Billingsley

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(27)

Published: March 5, 2024

Abstract Chimeric antigen receptor (CAR) monocyte and macrophage therapies are promising solid tumor immunotherapies that can overcome the challenges facing conventional CAR T cell therapy. mRNA lipid nanoparticles (mRNA‐LNPs) offer a viable platform for in situ engineering of monocytes with transient tunable expression to reduce off‐tumor toxicity streamline manufacturing. However, identifying LNPs tropism intracellular delivery potency is difficult using traditional screening techniques. Here, ionizable design high‐throughput vivo utilized identify new class oxidized innate monocytes. A library (oLNPs) unoxidized (uLNPs) synthesized evaluate immune cells. oLNPs demonstrate notable differences morphology, ionization energy, p K , thereby enhancing human macrophages, but not Subsequently, DNA barcodes identifies an oLNP formulation, C14‐O2, In proof‐of‐concept study, C14‐O2 LNP used engineer functional CD19‐CAR robust B aplasia (45%) healthy mice. This work highlights utility as macrophages/monocytes

Language: Английский

Citations

7
In Vitro Toxicity and Modeling Reveal Nanoplastic Effects on Marine Bivalves DOI
Yanfei Zhou, Xiaoxia Zhou, Hao Jiang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(26), P. 17228 - 17239

Published: June 15, 2024

Nanoplastics (NPs) represent a growing concern for global environmental health, particularly in marine ecosystems where they predominantly accumulate. The impact of NPs on benthic organisms, such as bivalves, raises critical questions regarding ecological integrity and food safety. Traditional methods assessing NP toxicity are often limited by their time-intensive nature ethical considerations. Herein, we explore the toxicological effects bivalve

Language: Английский

Citations

7