Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell-surface markers DOI Creative Commons

Bettina Dietmair,

James Humphries, Tim R. Mercer

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 17, 2024

Abstract Efficient delivery of mRNA-LNPs to specific cell-types remains a major challenge in the widespread application mRNA therapeutics. Conventional targeting approaches involve modifying lipid composition or functionalising surface nanoparticles (LNPs), which complicates manufacturing, alters nanoparticle size, charge and stealth, impacting their immunogenicity. Here we present generalisable method for targeted mRNA-LNP that uses bispecific antibodies (BsAbs) form bridge between LNPs cell-surface markers. Instead attaching agent nanocarrier, BsAbs are administered first, bind proteins on target cells, later retain unmodified affected tissues. We demonstrate efficient cell-type-specific epidermal growth factor receptor (EGFR), folate hydrolase 1 (PSMA) positive cells vitro vivo . The flexibility this technology, achieved by substitution cell-targeting region BsAbs, enables rapid development next-generation drugs.

Язык: Английский

Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism DOI Creative Commons
Mahboubeh Hosseini-Kharat, Kristen E. Bremmell, Clive A. Prestidge

и другие.

Molecular Therapy — Methods & Clinical Development, Год журнала: 2025, Номер 33(1), С. 101436 - 101436

Опубликована: Фев. 16, 2025

Lipid nanoparticles (LNPs) are now highly effective transporters of nucleic acids to the liver. This liver-specificity is largely due their association with certain serum proteins, most notably apolipoprotein E (ApoE), which directs them liver cells by binding low-density lipoprotein (LDL) receptors on hepatocytes. The liver's distinct anatomy, its various specialized cell types, also influences how LNPs taken up from circulation, cleared, and they in delivering treatments. In this review, we consider factors that facilitate LNP's targeting explore latest advances liver-targeted LNP technologies. Understanding targeted can help for design optimization nanoparticle-based therapies. Comprehension cellular interaction biodistribution not only leads better treatments diseases but delivers insight directing other tissues, potentially broadening range therapeutic applications.

Язык: Английский

Процитировано

5
Specific muscle targeted delivery of miR-130a loaded lipid nanoparticles: a novel approach to inhibit lipid accumulation in skeletal muscle and obesity DOI Creative Commons
Yingqian Wang, Zeqiang Ma, Lele Jiang

и другие.

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 3, 2025

Skeletal muscle lipid deposition is a key manifestation of obesity, often accompanied by decreased exercise capacity and atrophy. as the largest organ in body, makes it challenges for designing targeted drug delivery systems. Lipid nanoparticles (LNPs) are widely used safe efficient carrier, there limited research on LNPs that specifically target skeletal muscle. A LNP designed with five specific receptor complements its surface, which targets vivo mice, without off-target effects other tissues organs. MiR-130a, regulator PPARG, factor deposition, was encapsulated (LNP@miR-130a). In high-fat diet (HFD) LNP@miR-130a effectively reduced increased activity enhanced mass. Interestingly, myokines have also changed may leading to reduce adipose tissue weight liver HFD mice. These results indicated promising inhibitor help alleviate obesity. This study provides new insights obesity treatment lays foundation development therapeutics.

Язык: Английский

Процитировано

0
Model‐Informed Drug Development Applications and Opportunities in mRNA‐LNP Therapeutics DOI Creative Commons
Jiawei Zhou, Rohit Rao,

Mark Shapiro

и другие.

Clinical Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

The utilization of lipid nanoparticles (LNP) for encapsulating mRNA has revolutionized the field therapeutics, enabling rapid development COVID‐19 vaccines and cancer vaccines. However, clinical mRNA‐LNP therapeutics faces numerous challenges due to their complex mechanisms action limited experience. To overcome these hurdles, Model‐Informed Drug Development (MIDD) emerges as a valuable tool that can be applied facilitating evaluation safety efficacy through integration data from all stages into appropriate modeling simulation techniques. In this review, we provide an overview current MIDD applications in using vivo data. A variety methods are reviewed, including quantitative system pharmacology (QSP), physiologically based pharmacokinetics (PBPK), mechanistic pharmacokinetics/pharmacodynamics (PK/PD), population PK/PD, model‐based meta‐analysis (MBMA). Additionally, compare differences between mRNA‐based small interfering RNA, adeno‐associated virus‐based gene therapies terms pharmacology, discuss potential mutual sharing knowledge therapeutics. Furthermore, highlight promising future opportunities applying approaches drugs. By emphasizing importance throughout development, review aims encourage stakeholders recognize value its enhance

Язык: Английский

Процитировано

0
Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell-surface markers DOI Creative Commons

Bettina Dietmair,

James Humphries, Tim R. Mercer

и другие.

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(2), С. 102520 - 102520

Опубликована: Март 20, 2025

Efficient delivery of mRNA-lipid nanoparticles (LNPs) to specific cell types remains a major challenge for mRNA therapeutics. Conventional targeting approaches involve modifying the lipid composition or functionalizing surface LNPs, which complicates manufacturing and alters nanoparticle size, charge, stealth, impacting their immunogenicity. Here, we present generalizable method targeted mRNA-LNP that uses bispecific antibodies (BsAbs) form bridge between LNPs markers. BsAbs can be combined with administered first, binding proteins on target cells later retaining unmodified in affected tissues. We demonstrate efficient cell-type-specific mRNA-LNPs beyond liver, epidermal growth factor receptor (EGFR)- folate hydrolase 1 (PSMA)-positive vitro vivo. The flexibility this technology, achieved by substituting cell-targeting region BsAbs, enables rapid development next-generation drugs.

Язык: Английский

Процитировано

0
Circular RNAs modulate cancer drug resistance: advances and challenges DOI Open Access

Jinghan Hua,

Zhe Wang, Xiangfei Cheng

и другие.

Cancer Drug Resistance, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Acquired drug resistance is a main factor contributing to cancer therapy failure and high mortality, highlighting the necessity develop novel intervention targets. Circular RNAs (circRNAs), an abundant class of RNA molecules with closed loop structure, possess characteristics including stability, which provide unique advantages in clinical application. Growing evidence indicates that aberrantly expressed circRNAs are associated against various treatments, targeted therapy, chemotherapy, radiotherapy, immunotherapy. Therefore, targeting these aberrant may offer strategy improve efficiency therapy. Herein, we present summary most recently studied their regulatory roles on resistance. With advances artificial intelligence (AI)-based bioinformatics algorithms, could emerge as promising biomarkers targets

Язык: Английский

Процитировано

0
Engineered multi-domain lipid nanoparticles for targeted delivery DOI

Z. Liu,

J. Chen, Mingkun Xu

и другие.

Chemical Society Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This review introduces a four-domain framework to dissect engineered lipid nanoparticles (LNPs) rationally and explores their programmability, in vivo behavior, emerging AI-driven strategies for design, simulation, clinical translation.

Язык: Английский

Процитировано

0
Research progress on lipid nanoparticle messenger RNA delivery system DOI Creative Commons
Shun He, Shuai Liu

Journal of Zhejiang University (Medical Sciences), Год журнала: 2025, Номер unknown

Опубликована: Июнь 1, 2025

mRNA therapeutic is a biotechnology that involves delivering in vitro transcribed into specific cells to produce target proteins for the treatment or prevention of diseases. However, development therapeutics relies largely on delivery systems, and lipid nanoparticles (LNPs) represent most widely used carriers clinical applications. Composed ionizable lipids, phospholipids, cholesterol, polyethylene glycol-lipids, LNPs can address critical challenges drug development, such as poor vivo stability difficulty crossing biological barriers. Ultimately, enable safe, efficient, targeted liver, lung, spleen, so on. This review outlines roles four components delivery. Then it introduces various organs/tissues pancreas, bone marrow, placenta, using strategies antibody modification, structure alteration, specialized administration routes. Additionally, this discusses applications LNP-based disease treatment, aiming provide insights translation therapies further innovation LNP systems.

Язык: Английский

Процитировано

0
Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell-surface markers DOI Creative Commons

Bettina Dietmair,

James Humphries, Tim R. Mercer

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 17, 2024

Abstract Efficient delivery of mRNA-LNPs to specific cell-types remains a major challenge in the widespread application mRNA therapeutics. Conventional targeting approaches involve modifying lipid composition or functionalising surface nanoparticles (LNPs), which complicates manufacturing, alters nanoparticle size, charge and stealth, impacting their immunogenicity. Here we present generalisable method for targeted mRNA-LNP that uses bispecific antibodies (BsAbs) form bridge between LNPs cell-surface markers. Instead attaching agent nanocarrier, BsAbs are administered first, bind proteins on target cells, later retain unmodified affected tissues. We demonstrate efficient cell-type-specific epidermal growth factor receptor (EGFR), folate hydrolase 1 (PSMA) positive cells vitro vivo . The flexibility this technology, achieved by substitution cell-targeting region BsAbs, enables rapid development next-generation drugs.

Язык: Английский

Процитировано

1