Current Issue : July-September Volume : 2025 Issue Number : 3 Articles : 5 Articles
The rational design of multifunctional drug delivery systems capable of achieving precise drug release remains a huge challenge. Herein, we designed a stimuli-responsive dendritic-DNA-based nanohydrogel as a nanocarrier to achieve the co-delivery of doxorubicin and HMGN5 mRNA-targeting antisense oligonucleotides, thus achieving dual therapeutic effects. The nanocarrier, constructed from dendritic DNA with three crosslinking branches and one loading branch, formed biocompatible and programmable DNA nanohydrogels. The C-rich sequences in the crosslinking branches conferred pH sensitivity, while the loading strand enabled efficient incorporation of a shielding DNA/ASO complex. DOX encapsulation yielded a chemo–gene co-delivery platform. Upon cellular uptake by cancer cells, the nanocarrier disassembled in the acidic tumor microenvironment, releasing DOX for chemotherapy and ASOs via toehold-mediated strand displacement (TMSD) for targeted gene silencing. Cellular studies demonstrated significantly enhanced cancer cell inhibition compared to single-agent treatments, highlighting strong combined effects. This study provides a novel strategy for tumor-microenvironment-responsive codelivery, enabling precise, on-demand release of therapeutic agents to enhance combined chemo–gene therapy....
Nanoparticle-based mRNA delivery offers a versatile platform for innovative therapies. However, most of the current delivery systems are limited by poor serum tolerance, suboptimal endosomal escape and mRNA delivery efficacy. Herein, a highly efficient mRNA-delivering material is identified from a library of fluoropolymers. The lead material FD17 shows exceptional serum stability and endosomal escape, enabling efficient mRNA delivery into various cell types, surpassing commercial mRNA delivery reagents such as Lipofectamine 3000. The formed mRNA nanoparticles adsorb abundant serum albumin on the surface, which facilitates cellular uptake via scavenger receptor-mediated endocytosis. FD17 enables the delivery of mRNAs encoding CRE, Cas9, and base editor hyCBE for efficient genome editing. The material mediates CRISPR/Cas9 gene therapy via intraocular injection effectively down-regulates vascular endothelial growth factor A in retinal pigment epithelial cells of mice, yielding promising therapeutic responses against laser-induced choroidal neovascularization. The discovered material in this study shows great promise for the development of mRNA therapeutics to combat a wide range of diseases....
Autoimmune hepatitis (AIH) is a chronic liver disorder driven by immune dysregulation, marked by reduced regulatory T cells (Tregs) and unchecked inflammation. Current therapies lack specificity and efficacy, necessitating novel approaches. This study explores gene therapy using exosome-associated adeno-associated virus (exo-AAV) to deliver the Foxp3 gene, aiming to restore Treg-mediated immune tolerance in AIH. We engineered exosomes expressing the CD4-targeting antibody on their surface, encapsulating AAV6/Foxp3, to enhance lymphoid cell specificity. In a ConA-induced murine AIH model, engineered exo-AAV administration significantly increased hepatic Treg proportions while reducing Th17 cells and inflammatory cytokines (IFN-γ, TNF-α, IL-6), compared to control groups (unmodified exo-AAV or empty exosomes). Liver histopathology and serum ALT levels also improved in engineered exo-AAV treated mice. Mechanistically, engineered exo- AAV demonstrated superior targeting via CD4 binding, validated by immunofluorescence and nanoparticle tracking. Despite transient reductions in splenic Tregs, localized hepatic immune modulation underscored exo-AAV’s efficacy. These findings highlight engineered exo-AAV as a promising strategy for precision gene therapy in AIH, overcoming limitations of traditional AAV delivery by enhancing lymphocyte-specific transduction and immune balance restoration. This approach presents a novel therapeutic avenue for systemic autoimmune diseases reliant on Treg reinforcement....
Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 60–80% of all cases globally. Hallmark pathologies of AD include the accumulation of amyloid β peptide and phosphorylated tau, leading to neuronal circuit dysfunction, defective axonal transport, and neurotransmitter system (NTS) abnormalities. Disruptions in acetylcholine, GABA, dopamine, serotonin, and glutamate levels, as well as the loss of cholinergic, GABAergic, and monoaminergic neurons, contribute to the progression of AD. Additionally, neurotrophic factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are significantly reduced in AD, impacting neuronal health and synaptic integrity. This review highlights the emerging role of neurotrophic factor alpha 1 (NF-α1), also known as carboxypeptidase E, in AD. NF-α1 shows neuroprotective and neurogenesis-promoting properties, offering potential for therapeutic interventions. The review compares NF-α1 gene therapy with other neurotrophin-based treatments, providing insights into its efficacy in AD management....
Gene therapy holds great promise for treating various congenital rare diseases. However, immunogenicity against viral vectors used in gene therapy remains a challenge, impacting both the safety and efficacy of gene therapy products. Neutralizing antibodies against the vector capsid proteins impact the ability to re-dose patients, which a growing body of evidence suggests might be required for some indications and certain younger patient populations. In this communication, we report a novel dual-acting liposomal formulation that induces immune tolerance toward adeno-associated virus 9null (AAV9null) capsid proteins. We present in silico data on our first- and second-generation Tim agonist molecules as well as in vitro and in vivo data supporting the generation of antigen-specific regulatory T cells (Tregs) as well as abrogation of antibody response to AAV9null capsid in our animal models. These early data are encouraging and may offer a new solution to mitigate the immunogenicity induced by gene therapy products....
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