Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection DOI
Yonger Xue, Chang Wang, Haoyuan Li

et al.

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: May 3, 2025

Abstract Lipid nanoparticle‐messenger RNA formulations have garnered significant attention for their therapeutic potential in infectious diseases, cancer and genetic disorders. However, effective mRNA delivery to the central nervous system (CNS) remains a formidable challenge. To overcome this limitation, class of brain‐targeting lipids (BLs) is developed by incorporating small molecules with amino formulated them helper generate lipid nanoparticles (BLNPs) delivery. Screening studies led lead formulation, TD5 BLNPs, outperforming FDA‐approved DLin‐MC3‐DMA LNPs delivering brain upon intrathecal injection. Specifically, single injection BLNP‐GFP GFP expression 29.6% neurons 38.1% astrocytes across brain. In an Ai14 mouse model, BLNP‐Cre recombinase treatment induced tdTomato ≈30% 40% major regions. Notably, Cas9 mRNA/sgRNA complex using BLNPs achieved genome editing Additionally, showed comparable safety profiles MC3 LNPs, indicating promising biocompatibility. Overall, BLNP formulation effectively delivers tissues via facilitates efficient both astrocytes, presenting strategy treating CNS diseases.

Language: Английский

Machine learning-assisted design of immunomodulatory lipid nanoparticles for delivery of mRNA to repolarize hyperactivated microglia DOI Creative Commons
Mehrnoosh Rafiei, Akbar Shojaei, Ying Chau

et al.

Drug Delivery, Journal Year: 2025, Volume and Issue: 32(1)

Published: March 3, 2025

Regulating inflammatory microglia presents a promising strategy for treating neurodegenerative and autoimmune disorders, yet effective therapeutic agents delivery to these cells remains challenge. This study investigates modified lipid nanoparticles (LNP) mRNA hyperactivated microglia, particularly those with pro-inflammatory characteristics, utilizing supervised machine learning (ML) classifiers. We developed screened library of 216 LNP formulations varying compositions, N/P ratios, hyaluronic acid (HA) modifications. The transfection efficiency eGFP was assessed in the BV-2 murine cell line under different immunological states, including resting activated conditions (LPS-activated IL4/IL13-activated). ML-guided morphometric analysis tracked phenotypes various subtypes before after transfection. Four ML classifiers were investigated predict phenotypic changes based on design parameters. Multi-Layer Perceptron (MLP) neural network emerged as best-performing model, achieving weighted F1-scores ≥0.8. While it accurately predicted responses from LPS-activated cells, struggled IL4/IL13-activated cells. MLP model validated by predicting performance four unseen delivering BV2 HA-LNP2 optimal formulation target IL10 mRNA, effectively suppressing phenotypes, evidenced shifts morphology, increased expression, reduced TNF-α levels. also evaluated human iPSC-derived confirming its efficacy modulating responses. highlights potential tailored techniques enhance therapy neuroinflammatory disorders leveraging carrier's immunogenic properties modulate microglial

Language: Английский

Citations

0
Nanoparticles Designed Based on the Blood‐Brain Barrier for the Treatment of Cerebral Ischemia‐Reperfusion Injury DOI Open Access

Zhi‐Wei Du,

Yaosheng Li,

Xinchi Jiang

et al.

Small, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Cerebral ischemia-reperfusion injury (CI/RI) is currently considered a significant factor affecting the prognosis of ischemic stroke. The blood-brain barrier (BBB) plays multiple roles in treatment ofCI/RI. BBB leakage allows bloodborne toxins to exacerbate stroke pathology. Yet as physiological that separates blood from brain, also poses obstacle therapeutic drug delivery. Therefore, it essential consider both crossing and repairing process CI/RI. Leveraging exceptional benefits nanoparticles (NPs) for penetration targeted repair, numerous NPs are developed promising delivery platforms. Considering complex role CI/RI, this review delves into strategies designing cross BBB, focusing on peptide-modified NPs, cell-mediated cell membrane-derived BBB-modulating NPs. Additionally, summarizes design targeting endothelial cells (ECs), astrocytes, those aimed at regulating microenvironment repair BBB. On basis, reveals prospects challenges designed around CI/RI treatment. And highlights need combine permeability promotion nanoparticle based achieve more effective

Language: Английский

Citations

0
Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases DOI

Seyedeh Ghazal Moosavi,

Niloufar Rahiman, Mahmoud Reza Jaafari

et al.

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113641 - 113641

Published: March 1, 2025

Language: Английский

Citations

0
Overcoming immunotherapy resistance in glioblastoma: challenges and emerging strategies DOI Creative Commons
Mengmeng Fu, Bing Xue, Xiangshui Miao

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 28, 2025

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by rapid proliferation, extensive infiltration, significant intratumoral heterogeneity. Despite advancements conventional treatments, including surgery, radiotherapy, chemotherapy, prognosis for GBM patients remains poor, with a median survival of approximately 15 months. Immunotherapy has emerged as promising alternative; however, unique biological immunological features, its immunosuppressive microenvironment (TME) low mutational burden, render it resistant to many immunotherapeutic strategies. This review explores key challenges immunotherapy, focusing on immune evasion mechanisms, blood-brain barrier (BBB), TME. Immune checkpoint inhibitors CAR-T cells have shown promise preclinical models but limited clinical success due antigen heterogeneity, cell exhaustion, impaired trafficking across BBB. Emerging strategies, dual-targeting cells, engineered secreting therapeutic molecules, advanced delivery systems overcome BBB, show potential enhancing treatment efficacy. Addressing these crucial improving immunotherapy outcomes.

Language: Английский

Citations

0
Roles of METTL3 and NLRP3 in pyroptosis and prospects in SCIRI DOI Creative Commons
Xiaoqing Guan, Fengyi Zhang, Ning Zhang

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 1, 2025

Spinal cord ischemia-reperfusion injury (SCIRI) leads to severe neurological deficits, with pyroptosis emerging as a key driver of inflammation and neuronal death. Recent studies suggest that methyltransferase-like 3 (METTL3), critical RNA methyltransferase, may regulate the nucleotide-binding oligomerized structural domain-like receptor protein (NLRP3) inflammasome activation via N6-Methyladenosine (m6A) modification, yet direct evidence in SCIRI remains limited. This review synthesizes current knowledge on METTL3-NLRP3 axis pyroptosis, explores its therapeutic potential, identifies research gaps for future investigation.

Language: Английский

Citations

0
Remote Organ Damage Induced by Stroke: Molecular Mechanisms and Comprehensive Interventions DOI
Jie Wang, Sen Gao, Yue Cui

et al.

Antioxidants and Redox Signaling, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Significance: Damage after stroke is not only limited to the brain but also often occurs in remote organs, including heart, lung, liver, kidney, digestive tract, and spleen, which are frequently affected by complex pathophysiological changes. The organs human body closely connected, signals transmitted through various molecular substances could regulate changes of organs. Recent Advances: latest studies have shown that inflammatory response plays an important role organ damage stroke, can aggravate activating oxidative stress, sympathetic axis, hypothalamic disturbing immunological homeostasis. Remote cause brain, aggravating damage. Critical Issues: Therefore, in-depth exploration mechanisms adopting corresponding comprehensive intervention strategies become necessary reduce promote protection. Future Directions: strategy involves multifaceted treatment methods such as inflammation regulation, antioxidants, neural stem cell differentiation. It provides a promising alternative for recovery patients inspiration future research treatment. interconnected at level. Only levels we save protect greatest extent. Antioxid. Redox Signal. 00, 000-000.

Language: Английский

Citations

0
Lipid engineered nanomaterials: A novel paradigm shift for combating stroke DOI

Etikala Amulya,

D. Bahuguna,

M.P.S. Negi

et al.

Applied Materials Today, Journal Year: 2024, Volume and Issue: 38, P. 102194 - 102194

Published: April 15, 2024

Language: Английский

Citations

3
Transforming stroke treatment through nanotherapies DOI Creative Commons

Huiying Ouyang,

Yunfeng Mu,

Xing Zhou

et al.

Nanomedicine, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 4

Published: Jan. 28, 2025

KEYWORDS: Strokenanotherapynanomedicinenanoparticledrug deliverytargeted therapyinflammationoxidative stress

Language: Английский

Citations

0
Advancing CNS Therapeutics: Enhancing Neurological Disorders with Nanoparticle-Based Gene and Enzyme Replacement Therapies DOI Creative Commons
Shuhan Liu, Haisong Li,

Shiwen Xi

et al.

International Journal of Nanomedicine, Journal Year: 2025, Volume and Issue: Volume 20, P. 1443 - 1490

Published: Feb. 1, 2025

Abstract: Given the complexity of central nervous system (CNS) and diversity neurological conditions, increasing prevalence disorders poses a significant challenge to modern medicine. These disorders, ranging from neurodegenerative diseases psychiatric not only impact individuals but also place substantial burden on healthcare systems society. A major obstacle in treating these conditions is blood-brain barrier (BBB), which restricts passage therapeutic agents brain. Nanotechnology, particularly use nanoparticles (NPs), offers promising solution this challenge. NPs possess unique properties such as small size, large surface area, modifiable characteristics, enabling them cross BBB deliver drugs directly affected brain regions. This review focuses application gene therapy enzyme replacement (ERT) for disorders. Gene involves altering or manipulating expression can be enhanced by designed carry various genetic materials. Similarly, improve efficacy ERT lysosomal storage (LSDs) facilitating delivery brain, overcoming issues like immunogenicity instability. Taken together, explores potential revolutionizing treatment options highlighting their advantages future directions rapidly evolving field. Keywords: system, nanoparticle, therapy,

Language: Английский

Citations

0
Sustained Release of Dual p38 Inhibitors via Supramolecular Hydrogels to Enhance Cardiac Repair after MI/R Injury DOI Creative Commons
Di Wang,

Aoxue Xu,

Haitao Su

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Abstract Activation of p38 mitogen-activated protein kinase plays an important role in the progression ventricular muscle inflammation after myocardial ischemia-reperfusion (MI/R). The inhibition activation ischemic myocardium can reduce remodeling post-MI. However, owing to dynamic change MI, clinical therapeutic effect inhibitors is insufficient. Herein, we describe design a hydrogelator Nap-Phe-Phe-Thr-Gly-Tyr-OH (Nap-TGY) coassemble inhibitor SB202190 (SB), responsive supramolecular hydrogel (Gel Nap-TGY+SB) for local administration and release SB efficiently improve inflammatory microenvironment. Under overexpression myocardium, Nap-TGY phosphorylated yield hydrophilic Nap-Phe-Phe-Thr(H2PO3)-Gly-Tyr(H2PO3) (Nap-TpGYp), triggering disassembly inhibitor. Injection into significantly reduces phosphorylation, mitigates inflammation, enhances angiogenesis. These findings suggest novel strategy cardiomyopathy through modulation (MAPK) pathway.

Language: Английский

Citations

0