Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113837 - 113837
Опубликована: Май 1, 2025
Язык: Английский
Advanced Science, Год журнала: 2025, Номер unknown
Опубликована: Фев. 17, 2025
Abstract Lipid nanoparticles (LNPs) are clinically advanced delivery systems for RNA. The extensively developed structure of ionizable lipids greatly contributes to the functional mRNA. However, endosomal escape is one severe biological barriers that continue render this process inefficient (e.g., less than 10%). Although LNPs contain phospholipids, their role poorly understood, and there have been few attempts perform chemical engineering required improve functionality. Herein, a cubic phase‐inducible fusogenic zwitterionic phospholipid derived from 1,2‐dioleoyl‐3‐ sn ‐glycero‐phosphoethanolamine (DOPE), DOPE‐Cx described, designed correct problem. orientation head group DOPE engineered by attaching series hydrophobic moieties intermolecular interaction with phosphatidylcholine (PC), followed lipid‐phase transition into non‐lamellar phases facilitate membrane fusion‐mediated escape. A structure–activity relationship study reveals small chains induce instead hexagonal phase when mixed PC, which enhances mRNA in liver as opposed action typically utilized naturally occurring phospholipids. Engineered functionalized phospholipids will be great value therapeutic applications mRNAs.
Язык: Английский
Процитировано
1
International Journal of Pharmaceutics, Год журнала: 2025, Номер 674, С. 125427 - 125427
Опубликована: Март 11, 2025
Язык: Английский
Процитировано
1
International Journal of Pharmaceutics, Год журнала: 2025, Номер unknown, С. 125282 - 125282
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
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
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
Advanced Materials, Год журнала: 2025, Номер unknown
Опубликована: Март 27, 2025
Ischemic stroke represents one of the leading cerebrovascular diseases with a high rate mortality and disability globally. To date, there are no effective clinical drugs available to improve long-term outcomes for post-stroke patients. A novel nucleic acid agent circSCMH1 which can promote sensorimotor function recovery in rodent nonhuman primate animal models has been found. However, still delivery challenges overcome its implementation. Besides, effects on cognitive functions remain unexplored. Herein, lipid nanoparticle circSCMH1@LNP1 is established deliver explore therapeutic efficacy comprehensively. Distribution experiments demonstrate that intranasal administration significantly increases distribution peri-infarct region reduces non-specific accumulation other organs compared intravenous injection. Therapeutic results indicate promotes synaptic plasticity, vascular repair, neuroinflammation relief, myelin sheath formation, thereby achieving enhanced mice. In conclusion, this research presents simple LNP system efficient via repair brain injury. It envisioned study may bridge crucial gap between basic translational application, paving way implementation patient management.
Язык: Английский
Процитировано
0
Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)
Опубликована: Апрель 1, 2025
Extracellular particles (EPs), including extracellular vesicles (EVs) and non-vesicular (NVEPs), are multimolecular biomaterials released by cells that play a crucial role in intercellular communication. Recently, new subtypes of EPs associated with central nervous system (CNS), such as exophers supermeres have been identified. These provide perspectives for understanding the pathological progression CNS disorders confer potential diagnostic value liquid biopsies neurodegenerative diseases (NDs). Moreover, emerged promising drug delivery vehicles targeted platforms CNS-specific therapies. In this review, we delineate landscape EP their roles pathophysiology diseases. We also review recent advances EP-based diagnosis NDs highlight importance analytical single-particle resolution exploitation biomarkers. Furthermore, summarize application engineered EVs treatment outline underexplored NVEPs novel therapeutic agents.
Язык: Английский
Процитировано
0
Journal of the American Chemical Society, Год журнала: 2025, Номер 147(19), С. 16007 - 16017
Опубликована: Апрель 30, 2025
Delivery of mRNA (mRNA) to the central nervous system (CNS) remains a significant challenge. Herein, we design library furan-derived lipids and, our knowledge, for first time, leverage meningeal lymphatic vessels (MLVs) route achieve efficient delivery brain. These were engineered with different furan cores, functional groups, and tails. We found that tetrahydrofuran (THF)-derived lipid nanoparticles (LNPs) generally displayed exceptional compared their furan-based counterparts. Specifically, LNPs formulated four-acetal-tail mono-THF-derived F10T5 di-THF-derived F11T6 demonstrated significantly higher efficiency brain FDA-approved SM102 LNPs. The data revealed these bypassed blood-brain barrier (BBB) via pathway, traveling from deep cervical lymph nodes (dCLNs) meninges subsequently entering cells. Collectively, this work provides valuable insights into engineering exploring alternative approaches
Язык: Английский
Процитировано
0
Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113837 - 113837
Опубликована: Май 1, 2025
Язык: Английский
Процитировано
0