Specific muscle targeted delivery of miR-130a loaded lipid nanoparticles: a novel approach to inhibit lipid accumulation in skeletal muscle and obesity

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

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An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles—Nonclinical Considerations

International Journal of Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Nucleic acid drug delivery with lipid nanoparticle (LNP) formulations has enabled the development of novel therapeutics and vaccines. LNP are composed both naturally occurring synthetic excipients. This perspective shares current practices in nonclinical safety assessment excipients contained identifies gaps regulatory guidance on this topic. There is no globally harmonized for or specific to testing LNPs. Given complexity these formulations, most studies support conducted product a that contains non-active cargo. Three case (Onpattro®, Comirnaty®, SpikeVax®) highlight assessments may differ depending encapsulated modality, intended use (e.g., therapeutic versus preventative vaccine), dose, frequency dosing. These also suggest agencies open scientific rationale justify why certain tests should not be performed. As more products approved, it will important understand how precedents set approved can leveraged what additional unique strategies applied ensure predictive, relevant, meaningful human safety. Proactive alignment authorities critical context, especially as new approaches proposed. Guidance documents need revised created experience acquired reflect considerations

Язык: Английский

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Lipid-siRNA Organization Modulates the Intracellular Dynamics of Lipid Nanoparticles

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Lipid nanoparticles (LNPs) are widely used for delivering therapeutic nucleic acids, yet the relationship between their internal structure and intracellular behavior, particularly before RNA release, remains unclear. Here, we elucidate how lipid-siRNA organization within LNPs can modulate delivery dynamics. We use cryo-electron microscopy photochemical assays to reveal that increased siRNA loading reduce helper lipids' distribution LNP surface, while consistently localizes near surface. These alterations in affect membrane fluidity, enhancing fusion with cellular membranes promoting cytosolic delivery, primarily via macropinocytosis. Using photosensitive lipids live cell imaging, demonstrate regulates responsiveness external stimuli, significantly affecting endosomal escape efficiency upon light activation. further confirm this observation using convex lens-induced confinement single-particle imaging. Overall, our findings provide critical insights into shapes dynamics, offering rational design principles optimizing LNP-based therapeutics.

Язык: Английский

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Programmable mRNA therapeutics for controlled epigenomic modulation of single and multiplexed gene expression in diverse diseases

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 13, 2025

Pathogenic gene dysregulation can be attributed to chromatin state change that pre-transcriptionally regulates expression. Recent breakthroughs elucidating the rules governing this DNA control layer, an epigenetic code, unlock a modality in precision medicine target across myriad diseases. Here we present modular platform design programmable mRNA therapeutics, Epigenomic Controllers (EC), expression through directed change. By leveraging natural mechanisms, ECs tune levels of one or multiple genes with durable effect weeks-to-months female mice following single dose. We and characterize identify EC effectively inhibits cancer- inflammatory-disorder-associated multi-gene cluster CXCL1-8. With targeting NF-kB signaling identification homologous murine surrogates, significantly reduce neutrophil migration vivo during acute lung inflammation mice. A approach for epigenomic modulation expands treatment frontiers diverse targets, including those considered "undruggable." medicines hold enormous promise drugging targets outside reach classic small molecules. Here, authors develop therapeutics act by modifying state.

Язык: Английский

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Nanotechnological approaches in topical RNAi therapy for skin diseases

Academia Biology, Год журнала: 2025, Номер 3(1)

Опубликована: Март 18, 2025

The discovery of RNA interference (RNAi) has revolutionized molecular biology and therapeutic development, offering a novel approach to gene silencing. Despite significant progress, critical gap remains in fully harnessing the potential RNAi-based therapies for broader range diseases, particularly beyond hepatic targets. This review focuses on strategies overcome unique barriers posed by skin examines recent advances nanoparticle-based delivery systems RNAi targeting diseases. Nanoparticles (NPs)—including lipid-based, inorganic, polymer-based carriers—have demonstrated improved drug delivery, sustained release precise effects. Although several drugs have already been approved, further research is necessary expand their application Furthermore, innovative are crucial enhancing efficacy, overcoming barrier. findings indicate that despite considerable innovation NP design mechanisms essential exploit dermatology.

Язык: Английский

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