Mathematical Biosciences, Год журнала: 2025, Номер unknown, С. 109476 - 109476
Опубликована: Июнь 1, 2025
Current Opinion in Chemical Biology, Год журнала: 2024, Номер 81, С. 102506 - 102506
Опубликована: Авг. 1, 2024
Despite impressive recent establishment of therapeutic nucleic acids as drugs and vaccines, their broader medical use is impaired by modest performance in intracellular delivery. Inefficient endosomal escape presents a major limitation responsible for inadequate cytosolic cargo release. Depending on the carrier, this barrier can strongly limit or even abolish acid Different strategies hypothesized mechanisms are reviewed.
Язык: Английский
Процитировано
15
Advanced Healthcare Materials, Год журнала: 2025, Номер unknown
Опубликована: Янв. 22, 2025
Abstract Therapeutic strategy for efficiently targeting cancer cells needs an in‐depth understanding of the cellular and molecular interplay in tumor microenvironment (TME). TME comprises heterogeneous clustered together to translate initiation, migration, proliferation. The mainly proliferating cells, stromal blood vessels, lymphatic cancer‐associated fibroblasts (CAFs), extracellular matrix (ECM), stem (CSC). heterogeneity genetic evolution metastatic tumors can substantially impact clinical effectiveness therapeutic agents. Therefore, shall target all stages. Since advent nanotechnology, smart drug delivery strategies are employed deliver effective formulations directly into tumors, ensuring controlled sustained efficacy. state‐of‐the‐art nano‐drug systems shown have innocuous modes action players TME. this review provides insight mechanism metastasis involving invasion, intravasation, systemic transport circulating (CTCs), extravasation, colonization, angiogenesis. Further, novel perspectives associated with current nanotherapeutic highlighted on different stages metastasis.
Язык: Английский
Процитировано
1
European Journal of Pharmaceutical Sciences, Год журнала: 2024, Номер 205, С. 106983 - 106983
Опубликована: Дек. 7, 2024
Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated (Cas) protein has been proved as a powerful tool for the treatment of genetic diseases. The Cas9 protein, when combined with single-guide RNA (sgRNA), forms Cas9/sgRNA ribonucleoprotein (RNP) capable targeting and editing genome. However, limited availability effective carriers restricted broader application CRISPR/Cas9 RNP. In this study, we evaluated dual pH-responsive amphiphilic xenopeptides (XPs) delivering These artificial lipo-XPs contain apolar cationizable lipoamino fatty acid (LAF) polar oligoaminoethylene units such succinoyl-tetraethylenepentamine (Stp) in various ratios U-shaped topologies. were screened functional RNP delivery four different reporter cell lines, including Duchenne muscular dystrophy (DMD) exon skipping model. Significantly enhanced cellular uptake into HeLa cells, endosomal disruption gal8-mRuby3 potent genome by several complexes was observed lines 5 nM sgRNA range. Comparing mRNA/sgRNA polyplexes DMD model demonstrated similar splice site high two molecular modalities. Based on these studies, analogues U1 LAF2-Stp LAF4-Stp2 structures deployed, tuning amphiphilicity Stp group replacement six oligoamino acids dmGtp, chGtp, dGtp, Htp, Stt, or GEIPA. most (containing chGtp GEIPA) further gene efficiency EC50 values 1 line. Notably, LAF2-dGtp reached 0.51 even upon serum incubation. Another carrier (LAF4-GEIPA2) complexing donor DNA, facilitated up to 43 % homology-directed repair (HDR) eGFPd2 cells visualized switch from green fluorescent (eGFP) blue (BFP). This study presents system tunable RNP/donor DNA polyplexes, offering an easily applicable strategy editing.
Язык: Английский
Процитировано
4
Drug Delivery and Translational Research, Год журнала: 2024, Номер unknown
Опубликована: Сен. 19, 2024
Abstract Gastrointestinal disorders originate in the gastrointestinal tract (GIT), and therapies can benefit from direct access to GIT achievable through oral route. RNA molecules show great promise therapeutically but are highly susceptible degradation often require a carrier for cytoplasmic access. Lipid nanoparticles (LNPs) clinically proven drug-delivery agents, primarily administered parenterally. An ideal Orally Delivered (OrD) LNP formulation should overcome diverse GI environment, successfully delivering drug site of action. A versatile OrD has been developed encapsulate deliver siRNA mRNA this paper. The formulations were prepared by systematic addition cationic lipid base formulation, keeping total ionizable 50 mol%. Biorelevant media stability depicted increased resistance bile salt mediated destabilization upon lipid, however vitro efficacy data underscored importance lipid. Based on this, was selected comprising 20% 30% Further investigation revealed enhanced after incubation different dilutions fasted gastric, intestinal media, mucin. Confocal imaging flow cytometry confirmed uptake while vivo studies demonstrated with as payloads. Taken together, research introduces nucleic acid locally GIT. Graphical
Язык: Английский
Процитировано
3
Biochemistry, Год журнала: 2025, Номер unknown
Опубликована: Март 18, 2025
Efficient delivery of siRNA-based polyplexes to tumors remains a major challenge. Nonspecific interactions in the bloodstream, limited circulation time, and nontargeted biodistribution hamper sufficient tumor accumulation. To address these challenges, we developed an ionic hyaluronic acid (HA) coating shield sequence-defined oligoaminoamide-based polyplexes. This should positive polyplex surface charge, thus reducing nonspecific enhancing serum stability. Additionally, modified HA with cyclic RGDfK (cRGD) peptide specifically target endothelial cells (TECs). Optionally, polyethylene glycol (PEG) spacer was also introduced improve ligand presentation on surface. The HA-coated exhibited favorable physicochemical properties, including negative zeta potential effective siRNA retention within polyplex, which not adversely affected by PEG or cRGD modification. In vitro analyses revealed that only enhanced cell association preserved high transfection efficiency plain cationic but coating-dependent cellular internalization, as evidenced competitive inhibition experiment. Even presence serum, encapsulated effectively, suitable particle sizes, maintained gene silencing efficiency. vivo studies involving intravenous administration into Neuro2a tumor-bearing mice showed coating, particularly when cRGD, significantly increased accumulation HA–PEG–cRGD-shielded compared Collectively, our results indicate superior performance terms stability uptake, both vivo.
Язык: Английский
Процитировано
0
Bioconjugate Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Март 25, 2025
Although small interfering RNA (siRNA) holds immense promise for treating genetic diseases and cancers, its clinical application is constrained by instability, cellular uptake barriers, inefficient cytosolic delivery, underscoring the need effective delivery systems. Therefore, this study focuses on screening novel T-shaped lipo-xenopeptide (XP) nanocarriers siRNA polyplex formulation, integrating two single succinoyl-tetraethylene pentamine (Stp) units electrostatic interaction tyrosine tripeptides (Y3) aromatic stabilization, along with structural modifications such as addition of histidine (H) or without terminal cysteines (C), incorporation various fatty acids (FAs). A systematic evaluation binding, nanoparticle stability, gene silencing efficiency in multiple cell lines illustrated that Stp1-HC lipo-XPs carriers outperform their Stp2-HC analogs, despite having fewer cationizable Stp units. This advantage stems from increased acid, Y3, C density, which compensates reduced interactions. The presence H combination unsaturated FAs significantly improved functional delivery. Our findings highlight complex interplay electrostatic, hydrophobic, covalent, hydrogen-bonded, interactions to achieve efficient best-balanced oleic acid-containing Stp1-HC/OleA lipo-XP, exceeding previously best standard carrier Stp2-HC/OleA efficiency.
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Апрель 19, 2025
Abstract Endothelial cells (EC) comprise the pulmonary vascular bed and play a significant role in health disease. Consequently, EC niche represents an attractive therapeutic target for treating wide range of diseases. We have identified new class dicationic Charge-Altering Releasable Transporters. These single-component transporters selectively deliver mRNA to lung upon intravenous administration without use targeting ligand. Significantly, number spatial array cationic charges within repeating units CART polymer are found control both delivery efficacy tissue tropism. High-resolution imaging revealed efficient endothelial arteries, veins capillaries. The selective tropism these CARTs, coupled with tunable synthesis this family amphiphiles, enabling platform research clinical applications.
Язык: Английский
Процитировано
0
Journal of Drug Delivery Science and Technology, Год журнала: 2025, Номер unknown, С. 106995 - 106995
Опубликована: Май 1, 2025
Язык: Английский
Процитировано
0
Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)
Опубликована: Май 30, 2025
Язык: Английский
Процитировано
0
Mathematical Biosciences, Год журнала: 2025, Номер unknown, С. 109476 - 109476
Опубликована: Июнь 1, 2025
Процитировано
0