Project description:Immune system responses against adeno-associated virus (AAV) vectors are potentiated after the first administration, which has prevented the clinical use of repeated administration of AAV-based gene therapies. Here, we quantify the contributions of multiple immune system components towards AAV response in mice. We identify B-cell-mediated immunity, specifically the generation of IgM antibodies, as a critical component preventing vector re-administration.
Project description:Dendrimer-targeted immunosuppression of microglia reactivity further enhances promotes photoreceptor regeneration kinetics in the zebrafish retina
Project description:Nanoparticles and nano delivery systems are continuously being refined and developed as means of treating numerous human diseases by site-specific, and target-oriented delivery of medicines. The nanoparticles can carry therapeutic cargo or be medicinal themselves by virtue of their constitutional structural components. Here we report the ability of synthetic N-acylethanolamides, linoleoylethanolamide (LEA) and oleoylethanolamide (OEA), with endocannabinoid-like activity, to form spherical colloidal nanoparticles that when conjugated with tissue specific homing molecules, can localise to specific areas of the body, and reduce inflammation. The opportunities to mediate pharmacological effects of endocannabinoids at targeted sites provides a novel drug delivery system with increased medicinal potential to treat many diseases in many areas of medicine.
Project description:CRISPR-based epigenome editing was recently used to activate gene expression through direct transcriptional activation or site-specific DNA demethylation. Viral delivery of guide RNAs for these purposes remains to be developed. Furthermore, currently available viral delivery tools for genome editing show meager rates of heritability. Here, we have developed a tobacco rattle virus (TRV)-based guide RNA delivery system for both transcriptional activation and targeted DNA demethylation. To promote heritable epigenome editing specifically within plant meristems and the germline, we used the tRNA-guide RNA expression system to express guide RNAs from the viral genome, thus facilitating cell-to-cell movement of the RNA in plants. We achieved up to ~8% heritability of the induced phenotype in the progeny of virus-inoculated plants and 25% in the following generation, indicating high rates of heritability for targeted DNA demethylation. Thus, TRV delivery, in combination with a specific tRNA-gRNA architecture, provides for fast and effective epigenome editing.
Project description:Cance vaccines have become a milestone in immunotherapy, but inadequate activation rate of antigen presenting cells (APCs) and low delivery efficiency of specific antigen have widely limited their clinical application. Here we design an engineered vaccine platform based on targeted delivery of specific antigens to activated APCs. This vaccine platform is implemented by loading stimulator of interferon genes agonist and tumor lysate protein with calcium phosphate as adjuvants, and coating the surface with mannose-modified liposomes. By loading different types of tumor antigen proteins, this nanovaccine platform successfully achieves tumor immunotherapy in breast and colon cancer bearing mice. In addition, personalized nanovaccine prepared from surgically removed tumor lysate proteins also significantly suppresses postsurgical distant tumor. Through the design of nanovaccine platform, we provide an efficient multi-adjuvant delivery platform for multiple types of tumor antigens, and also offer more ideas for personalized vaccine immunization. This nanovaccine platform has great prospects for transformation due to the designability and simplicity for the preparation.
Project description:Recent studies have highlighted the pivotal role of the cGAS-STING pathway in cancer immunotherapy. However, clinical trials with cGAS-STING pathway agonists have faced setbacks thanks to their short biological half-life, lack of specificity, and potential to promote tumor immune evasion. To address these challenges, we developed a novel drug delivery platform, termed cmExoaCD11b, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b was engineered to encapsulate high copy numbers of cGAMP and IL-12 mRNA using cellular nanoporation technology and was functionalized with anti-CD11b antibodies for targeted delivery to macrophages. Notably, cmExoaCD11b facilitates the repolarization of M2 macrophages to M1 phenotype, thereby reprograming the TME and enhancing the release of pro-inflammatory cytokines. cmExoaCD11b successfully reversed the immunosuppressive status in the TME and suppressed tumor growth. More importantly, cmExoaCD11b has demonstrated significant therapeutic efficacy in both murine pancreatic cancer models and patient-derived xenograft models. These results suggest that cmExoaCD11b represents a promising approach to overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.
Project description:Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) poses a significant clinical challenge due to its high morbidity and mortality, coupled with a lack of effective targeted therapies. Here, utilizing single-cell transcriptomic analysis, we identified integrin and CD44 as markedly upregulated in injured alveolar type II cells and myofibroblasts, highlighting their potential as pathological delivery targets in AE-IPF. Based on these findings, we developed a dual-targeted liposomal nanoplatform (ND-RHL) co-encapsulating nintedanib and dexamethasone, specifically engineered to exploit integrin/CD44 overexpression for pulmonary precise drug delivery and synergistic anti-fibrotic and anti-inflammatory effects. ND-RHL exhibited favorable physicochemical characteristics, efficient dual-drug loading, and selective accumulation in integrin/CD44-high cells both in vitro and in vivo. In a murine model of AE-PF, intratracheal administration of ND-RHL markedly improved survival, mitigated lung inflammation and fibrosis, and preserved pulmonary architecture, with minimal systemic toxicity. Mechanistically, transcriptomic profiling and immune phenotyping demonstrated that ND-RHL reversed AE-induced gene expression patterns and inhibited pivotal signaling pathways, including PI3K–AKT–mTOR, Wnt/β-catenin, and NF-κB–PPARγ, thereby orchestrating the remodeling of both immune and extracellular matrix microenvironments. This study presents ND-RHL as a mechanistically informed, cell-targeted nanotherapeutic with robust therapeutic potential and translational promise for the treatment of AE-IPF and related fibrotic lung diseases.