Pub Date : 2024-08-22DOI: 10.1016/j.jconrel.2024.08.012
Liver fibrosis is characterized by abnormal accumulation of extracellular matrix proteins, disrupting normal liver function. Despite its significant health impact, effective treatments remain limited. Here, we present the development of engineered lipid nanoparticles (LNPs) for targeted RNA therapeutic delivery in the liver. We investigated the therapeutic potential of modulating the G2 and S-phase expressed 1 (GTSE1) protein for treating liver fibrosis. Through screening, we identified P138Y LNP as a potent candidate with superior delivery efficiency and lower toxicity. Using these engineered LNPs, we successfully delivered siGTSE1 to hepatocytes, significantly reducing collagen accumulation and restoring liver function in a fibrosis animal model. Additionally, GTSE1 downregulation altered miRNA expression and upregulated hepatocyte nuclear factor 4 alpha (HNF4α). These findings suggest that therapeutic gene silencing of GTSE1 is a promising strategy for treating liver fibrosis by regenerating liver phenotypes and functions.
{"title":"Engineered lipid nanoparticles enable therapeutic gene silencing of GTSE1 for the treatment of liver fibrosis","authors":"","doi":"10.1016/j.jconrel.2024.08.012","DOIUrl":"10.1016/j.jconrel.2024.08.012","url":null,"abstract":"<div><p>Liver fibrosis is characterized by abnormal accumulation of extracellular matrix proteins, disrupting normal liver function. Despite its significant health impact, effective treatments remain limited. Here, we present the development of engineered lipid nanoparticles (LNPs) for targeted RNA therapeutic delivery in the liver. We investigated the therapeutic potential of modulating the G2 and S-phase expressed 1 (GTSE1) protein for treating liver fibrosis. Through screening, we identified P13<img>8Y LNP as a potent candidate with superior delivery efficiency and lower toxicity. Using these engineered LNPs, we successfully delivered siGTSE1 to hepatocytes, significantly reducing collagen accumulation and restoring liver function in a fibrosis animal model. Additionally, GTSE1 downregulation altered miRNA expression and upregulated hepatocyte nuclear factor 4 alpha (HNF4α). These findings suggest that therapeutic gene silencing of GTSE1 is a promising strategy for treating liver fibrosis by regenerating liver phenotypes and functions.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.jconrel.2024.08.018
mRNA-based vaccines symbolize a new paradigm shift in personalized medicine for the treatment of infectious and non-infectious diseases. However, the reactogenicity associated with the currently approved formulations limits their applicability in autoinflammatory disorders, such as tumour therapeutics. In this study, we present a delivery system showing controlled immunogenicity and minimal non-specific inflammation, allowing for selective delivery of mRNA to antigen presenting cells (APCs) within the medullary region of the lymph nodes. Our platform offers precise control over the trafficking of nanoparticles within the lymph nodes by optimizing stealth and targeting properties, as well as the subsequent opsonization process. By targeting specific cells, we observed a potent adaptive and humoral immune response, which holds promise for preventive and therapeutic anti-tumoral vaccines. Through spatial programming of nanoparticle distribution, we can promote robust immunization, thus improving and expanding the utilization of mRNA vaccines. This innovative approach signifies a remarkable step forward in the field of targeted nanomedicine.
{"title":"Stealth mRNA nanovaccines to control lymph node trafficking","authors":"","doi":"10.1016/j.jconrel.2024.08.018","DOIUrl":"10.1016/j.jconrel.2024.08.018","url":null,"abstract":"<div><p>mRNA-based vaccines symbolize a new paradigm shift in personalized medicine for the treatment of infectious and non-infectious diseases. However, the reactogenicity associated with the currently approved formulations limits their applicability in autoinflammatory disorders, such as tumour therapeutics. In this study, we present a delivery system showing controlled immunogenicity and minimal non-specific inflammation, allowing for selective delivery of mRNA to antigen presenting cells (APCs) within the medullary region of the lymph nodes. Our platform offers precise control over the trafficking of nanoparticles within the lymph nodes by optimizing stealth and targeting properties, as well as the subsequent opsonization process. By targeting specific cells, we observed a potent adaptive and humoral immune response, which holds promise for preventive and therapeutic anti-tumoral vaccines. Through spatial programming of nanoparticle distribution, we can promote robust immunization, thus improving and expanding the utilization of mRNA vaccines. This innovative approach signifies a remarkable step forward in the field of targeted nanomedicine.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0168365924005571/pdfft?md5=3668865831021e3eea666698f4124a7d&pid=1-s2.0-S0168365924005571-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.jconrel.2024.07.043
Extracellular vesicles (EVs), or exosomes, play important roles in physiological and pathological cellular communication and have gained substantial traction as biological drug carriers. EVs contain both short and long non-coding RNAs that regulate gene expression and epigenetic processes. To fully capitalize on the potential of EVs as drug carriers, it is important to study and understand the intricacies of EV function and EV RNA-based communication. Here we developed a genetically encodable RNA-based biomaterial, termed EXO-Probe, for tracking EV RNAs. The EXO-Probe comprises an EV-loading RNA sequence (EXO-Code), fused to a fluorogenic RNA Mango aptamer for RNA imaging. This fusion construct allowed the visualization and tracking of EV RNA and colocalization with markers of multivesicular bodies; imaging RNA within EVs, and non-destructive quantification of EVs. Overall, the new RNA-based biomaterial provides a useful and versatile means to interrogate the role of EVs in cellular communication via RNA trafficking to EVs and to study cellular sorting decisions. The system will also help lay the foundation to further improve the therapeutic efficacy of EVs as drug carriers.
细胞外囊泡(EVs)或外泌体(exosomes)在生理和病理细胞通讯中发挥着重要作用,并作为生物药物载体得到了广泛关注。EVs含有调节基因表达和表观遗传过程的长短非编码RNA。要充分利用 EVs 作为药物载体的潜力,就必须研究和了解 EV 功能和 EV RNA 通信的复杂性。在这里,我们开发了一种基于 RNA 的基因编码生物材料,称为 EXO-探针,用于追踪 EV RNA。EXO-Probe由EV载体RNA序列(EXO-Code)和用于RNA成像的荧光RNA Mango适配体融合而成。这种融合构建物允许可视化和跟踪 EV RNA,并与多囊体标记物共定位;对 EV 内的 RNA 进行成像,并对 EV 进行非破坏性量化。总之,这种基于 RNA 的新型生物材料提供了一种有用的多功能手段,可通过 RNA 向 EVs 的迁移来探究 EVs 在细胞通讯中的作用,并研究细胞的分拣决策。该系统还将有助于为进一步提高 EVs 作为药物载体的治疗效果奠定基础。
{"title":"Fluorogenic RNA-based biomaterials for imaging and tracking the cargo of extracellular vesicles","authors":"","doi":"10.1016/j.jconrel.2024.07.043","DOIUrl":"10.1016/j.jconrel.2024.07.043","url":null,"abstract":"<div><p>Extracellular vesicles (EVs), or exosomes, play important roles in physiological and pathological cellular communication and have gained substantial traction as biological drug carriers. EVs contain both short and long non-coding RNAs that regulate gene expression and epigenetic processes. To fully capitalize on the potential of EVs as drug carriers, it is important to study and understand the intricacies of EV function and EV RNA-based communication. Here we developed a genetically encodable RNA-based biomaterial, termed EXO-Probe, for tracking EV RNAs. The EXO-Probe comprises an EV-loading RNA sequence (EXO-Code), fused to a fluorogenic RNA Mango aptamer for RNA imaging. This fusion construct allowed the visualization and tracking of EV RNA and colocalization with markers of multivesicular bodies; imaging RNA within EVs, and non-destructive quantification of EVs. Overall, the new RNA-based biomaterial provides a useful and versatile means to interrogate the role of EVs in cellular communication via RNA trafficking to EVs and to study cellular sorting decisions. The system will also help lay the foundation to further improve the therapeutic efficacy of EVs as drug carriers.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.jconrel.2024.08.016
Lipid nanoparticle (LNP) formulation plays a vital role in RNA vaccine delivery. However, further optimisation of self-amplifying RNA (saRNA) vaccine formulation could help enhance seroconversion rates in humans and improve storage stability. Altering either the ionisable or helper lipid can alter the characteristics and performance of formulated saRNA through the interplay of the phospholipid's packing parameter and the geometrical shape within the LNP membrane. In this study, we compared the impact of three helper lipids (DSPC, DOPC, or DOPE) used with two different ionisable lipids (MC3 and C12–200) on stability, transfection efficiency and the inflammation and immunogenicity of saRNA. While helper lipid identity altered saRNA expression across four cell lines in vitro, this was not predictive of an ex vivo or in vivo response. The helper lipid used influenced LNP storage where DSPC provided the best stability profile over four weeks at 2–8 °C. Importantly, helper lipid impact on LNP storage stability was the best predictor of expression in human skin explants, where C12–200 in combination with DSPC provided the most durable expression. C12–200 LNPs also improved protein expression (firefly luciferase) and humoral responses to a SARS-CoV-2 spike saRNA vaccine compared to MC3 LNPs, where the effect of helper lipids was less apparent. Nevertheless, the performance of C12–200 in combination with DSPC appears optimal for saRNA when balancing preferred storage stability requirements against in vivo and ex vivo potency. These data suggest that helper lipid influences the stability and functionality of ionisable lipid nanoparticle-formulated saRNA.
{"title":"The role of helper lipids in optimising nanoparticle formulations of self-amplifying RNA","authors":"","doi":"10.1016/j.jconrel.2024.08.016","DOIUrl":"10.1016/j.jconrel.2024.08.016","url":null,"abstract":"<div><p>Lipid nanoparticle (LNP) formulation plays a vital role in RNA vaccine delivery. However, further optimisation of self-amplifying RNA (saRNA) vaccine formulation could help enhance seroconversion rates in humans and improve storage stability. Altering either the ionisable or helper lipid can alter the characteristics and performance of formulated saRNA through the interplay of the phospholipid's packing parameter and the geometrical shape within the LNP membrane. In this study, we compared the impact of three helper lipids (DSPC, DOPC, or DOPE) used with two different ionisable lipids (MC3 and C12–200) on stability, transfection efficiency and the inflammation and immunogenicity of saRNA. While helper lipid identity altered saRNA expression across four cell lines <em>in vitro</em>, this was not predictive of an <em>ex vivo</em> or <em>in vivo</em> response. The helper lipid used influenced LNP storage where DSPC provided the best stability profile over four weeks at 2–8 °C. Importantly, helper lipid impact on LNP storage stability was the best predictor of expression in human skin explants, where C12–200 in combination with DSPC provided the most durable expression. C12–200 LNPs also improved protein expression (firefly luciferase) and humoral responses to a SARS-CoV-2 spike saRNA vaccine compared to MC3 LNPs, where the effect of helper lipids was less apparent. Nevertheless, the performance of C12–200 in combination with DSPC appears optimal for saRNA when balancing preferred storage stability requirements against <em>in vivo</em> and <em>ex vivo</em> potency. These data suggest that helper lipid influences the stability and functionality of ionisable lipid nanoparticle-formulated saRNA.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0168365924005558/pdfft?md5=fcc163df6f7b460d08e58c43a6583e11&pid=1-s2.0-S0168365924005558-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.jconrel.2024.08.019
The persistent presence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei poses a significant obstacle to achieving a comprehensive cure for hepatitis B virus (HBV). Current applications of CRISPR/Cas9 for targeting and eliminating cccDNA have been confined to in vitro studies due to challenges in stable cccDNA expression in animal models and the limited non-immunogenicity of delivery systems. This study addresses these limitations by introducing a novel non-viral gene delivery system utilizing Gemini Surfactant (GS). The developed system creates stable and targeted CRISPR/Cas9 nanodrugs with a negatively charged surface through modification with red blood cell membranes (RBCM) or hepatocyte membranes (HCM), resulting in GS-pDNA@Cas9-CMs complexes. These GS-pDNA complexes demonstrated complete formation at a 4:1 w/w ratio. The in vitro transfection efficiency of GS-pDNA-HCM reached 54.61%, showing homotypic targeting and excellent safety. Additionally, the study identified the most effective single-guide RNA (sgRNA) from six sequences delivered by GS-pDNA@Cas9-HCM. Using GS-pDNA@Cas9-HCM, a significant reduction of 96.47% in in vitro HBV cccDNA and a 52.34% reduction in in vivo HBV cccDNA were observed, along with a notable decrease in other HBV-related markers. The investigation of GS complex uptake by AML-12 cells under varied time and temperature conditions revealed clathrin-mediated endocytosis (CME) for GS-pDNA and caveolin-mediated endocytosis (CVME) for GS-pDNA-HCM and GS-pDNA-RBCM. In summary, this research presents biomimetic gene-editing nanovectors based on GS (GS-pDNA@Cas9-CMs) and explores their precise and targeted clearance of cccDNA using CRISPR/Cas9, demonstrating good biocompatibility both in vitro and in vivo. This innovative approach provides a promising therapeutic strategy for advancing the cure of HBV.
{"title":"Enhanced delivery of CRISPR/Cas9 system based on biomimetic nanoparticles for hepatitis B virus therapy","authors":"","doi":"10.1016/j.jconrel.2024.08.019","DOIUrl":"10.1016/j.jconrel.2024.08.019","url":null,"abstract":"<div><p>The persistent presence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei poses a significant obstacle to achieving a comprehensive cure for hepatitis B virus (HBV). Current applications of CRISPR/Cas9 for targeting and eliminating cccDNA have been confined to in vitro studies due to challenges in stable cccDNA expression in animal models and the limited non-immunogenicity of delivery systems. This study addresses these limitations by introducing a novel non-viral gene delivery system utilizing Gemini Surfactant (GS). The developed system creates stable and targeted CRISPR/Cas9 nanodrugs with a negatively charged surface through modification with red blood cell membranes (RBCM) or hepatocyte membranes (HCM), resulting in GS-pDNA@Cas9-CMs complexes. These GS-pDNA complexes demonstrated complete formation at a 4:1 <em>w</em>/<em>w</em> ratio. The in vitro transfection efficiency of GS-pDNA-HCM reached 54.61%, showing homotypic targeting and excellent safety. Additionally, the study identified the most effective single-guide RNA (sgRNA) from six sequences delivered by GS-pDNA@Cas9-HCM. Using GS-pDNA@Cas9-HCM, a significant reduction of 96.47% in in vitro HBV cccDNA and a 52.34% reduction in in vivo HBV cccDNA were observed, along with a notable decrease in other HBV-related markers. The investigation of GS complex uptake by AML-12 cells under varied time and temperature conditions revealed clathrin-mediated endocytosis (CME) for GS-pDNA and caveolin-mediated endocytosis (CVME) for GS-pDNA-HCM and GS-pDNA-RBCM. In summary, this research presents biomimetic gene-editing nanovectors based on GS (GS-pDNA@Cas9-CMs) and explores their precise and targeted clearance of cccDNA using CRISPR/Cas9, demonstrating good biocompatibility both in vitro and in vivo. This innovative approach provides a promising therapeutic strategy for advancing the cure of HBV.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.jconrel.2024.08.025
Controlled-release systems enhance anti-tumor effects by leveraging local antigen persistence for antigen-presenting cells (APCs) recruitment and T cell engagement. However, constant antigen presentation alone tends to induce dysfunction in tumor-specific CD8+ T cells, neglecting the synergistic effects of co-stimulatory signal. To address this, we developed a soft particle-stabilized emulsion (SPE) to deliver lipopeptides with controlled release profiles by adjusting their hydrophobic chain lengths: C6-SPE (fast release), C10-SPE (medium release), and C16-SPE (slow release). Following administration, C6-SPE release antigen rapidly, inducing early antigen presentation, whereas C16-SPE's slow-release delays antigen presentation. Both scenarios missed the critical window for coordinating with the expression of CD86, leading to either T cell apoptosis or suboptimal activation. In contrast, C10-SPE achieved a spatiotemporally synergetic effect of the MHC-I-peptide complex and co-stimulatory signal (CD86), leading to effective dendritic cell (DC) activation, enhanced T cell activation, and tumor regression in EG7-OVA bearing mice. Additionally, co-delivery of cytosine-phosphate-guanine (CpG) with SPE provided a sustained expression of the CD86 window for DC activation, improving the immune response and producing robust anti-tumor effects with C6-SPE comparable to C10-SPE. These findings highlight that synchronizing the spatiotemporal dynamics of antigen presentation and APC activation may confer an optimal strategy for enhanced vaccinations.
控释系统利用局部抗原的持久性促进抗原递呈细胞(APCs)的招募和T细胞的参与,从而增强抗肿瘤效果。然而,单纯的持续抗原递呈往往会诱发肿瘤特异性 CD8+ T 细胞的功能障碍,而忽略了协同刺激信号的协同效应。为了解决这个问题,我们开发了一种软颗粒稳定乳液(SPE),通过调整疏水链长度来递送具有可控释放特性的脂肽:C6-SPE(快速释放)、C10-SPE(中等释放)和C16-SPE(缓慢释放)。给药后,C6-SPE 会快速释放抗原,诱导早期抗原呈递,而 C16-SPE 的缓释则会延迟抗原呈递。这两种情况都错过了与 CD86 表达协调的关键窗口期,导致 T 细胞凋亡或激活效果不佳。相比之下,C10-SPE 实现了 MHC-I 肽复合物和共刺激信号(CD86)的时空协同效应,从而有效激活了树突状细胞(DC),增强了 T 细胞的激活,并使携带 EG7-OVA 的小鼠肿瘤消退。此外,与 SPE 共同递送胞嘧啶-磷酸鸟嘌呤(CpG)为 DC 激活提供了一个持续表达 CD86 的窗口,改善了免疫反应,C6-SPE 产生的抗肿瘤效果与 C10-SPE 不相上下。这些发现突出表明,使抗原呈递和APC活化的时空动态同步可能是增强疫苗接种的最佳策略。
{"title":"Spatiotemporal coordination of antigen presentation and co-stimulatory signal for enhanced anti-tumor vaccination","authors":"","doi":"10.1016/j.jconrel.2024.08.025","DOIUrl":"10.1016/j.jconrel.2024.08.025","url":null,"abstract":"<div><p>Controlled-release systems enhance anti-tumor effects by leveraging local antigen persistence for antigen-presenting cells (APCs) recruitment and T cell engagement. However, constant antigen presentation alone tends to induce dysfunction in tumor-specific CD8<sup>+</sup> T cells, neglecting the synergistic effects of co-stimulatory signal. To address this, we developed a soft particle-stabilized emulsion (SPE) to deliver lipopeptides with controlled release profiles by adjusting their hydrophobic chain lengths: C<sub>6</sub>-SPE (fast release), C<sub>10</sub>-SPE (medium release), and C<sub>16</sub>-SPE (slow release). Following administration, C<sub>6</sub>-SPE release antigen rapidly, inducing early antigen presentation, whereas C<sub>16</sub>-SPE's slow-release delays antigen presentation. Both scenarios missed the critical window for coordinating with the expression of CD86, leading to either T cell apoptosis or suboptimal activation. In contrast, C<sub>10</sub>-SPE achieved a spatiotemporally synergetic effect of the MHC-I-peptide complex and co-stimulatory signal (CD86), leading to effective dendritic cell (DC) activation, enhanced T cell activation, and tumor regression in EG7-OVA bearing mice. Additionally, co-delivery of cytosine-phosphate-guanine (CpG) with SPE provided a sustained expression of the CD86 window for DC activation, improving the immune response and producing robust anti-tumor effects with C<sub>6</sub>-SPE comparable to C<sub>10</sub>-SPE. These findings highlight that synchronizing the spatiotemporal dynamics of antigen presentation and APC activation may confer an optimal strategy for enhanced vaccinations.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.jconrel.2024.08.023
Biologics have been widely used as injectables in the treatment of inflammatory bowel disease (IBD). Different local treatment attempts have been developed in recent years. However, maintaining systemic levels of biologics is still crucial for achieving colitis remission. An equilibrium between systemic and local concentrations of biologics is therefore essential for treatment of colitis. Current formulations struggle to create optimal balance between drug concentrations in plasma and the colonic wall. Addressing this challenge, we developed a rectally delivered in situ foam that generates CO2via a reaction between potassium bicarbonate (PB) and citric acid (CA) without the aid of an external device. An anti-TNF-α antibody fragment (Fab) was loaded into the foam formulation, which promoted prolonged colon retention and improved Fab distribution up to proximal colon following rectal administration to mice. In addition, we observed increased plasma Fab concentrations in mice receiving the rectal Fab foam compared to a Fab solution. In a non-everted rat gut ex vivo model, a single exposure to the CO2-containing foam improved macromolecule transepithelial flux across colonic tissue by over ten-fold. Foam efficacy for Fab was investigated in a range of colitis mouse models, from acute to chronic. This non-invasive formulation platform demonstrates potential to overcome existing limitations in delivering biologics to inflamed colonic tissue.
生物制剂作为注射剂已被广泛用于治疗炎症性肠病(IBD)。近年来,已开发出不同的局部治疗尝试。然而,维持生物制剂的全身水平对于实现结肠炎缓解仍然至关重要。因此,平衡生物制剂在全身和局部的浓度对于治疗结肠炎至关重要。目前的配方很难在血浆和结肠壁的药物浓度之间达到最佳平衡。为了应对这一挑战,我们开发了一种直肠给药原位泡沫,它可以通过碳酸氢钾(PB)和柠檬酸(CA)之间的反应生成二氧化碳,而无需借助外部设备。在泡沫配方中加入抗肿瘤坏死因子-α抗体片段(Fab),可促进小鼠直肠给药后延长结肠保留时间并改善 Fab 在结肠近端的分布。此外,与 Fab 溶液相比,我们观察到直肠给药泡沫小鼠的血浆 Fab 浓度有所提高。在非退行性大鼠肠道体外模型中,单次接触含二氧化碳的泡沫可使大分子通过结肠组织的上皮通量提高 10 倍以上。在一系列结肠炎小鼠模型(从急性到慢性)中对泡沫法布的功效进行了研究。这种非侵入性制剂平台展示了克服将生物制剂输送到发炎结肠组织的现有限制的潜力。
{"title":"An in situ bioadhesive foam as a large intestinal delivery platform for antibody fragment to treat inflammatory bowel disease","authors":"","doi":"10.1016/j.jconrel.2024.08.023","DOIUrl":"10.1016/j.jconrel.2024.08.023","url":null,"abstract":"<div><p>Biologics have been widely used as injectables in the treatment of inflammatory bowel disease (IBD). Different local treatment attempts have been developed in recent years. However, maintaining systemic levels of biologics is still crucial for achieving colitis remission. An equilibrium between systemic and local concentrations of biologics is therefore essential for treatment of colitis. Current formulations struggle to create optimal balance between drug concentrations in plasma and the colonic wall. Addressing this challenge, we developed a rectally delivered <em>in situ</em> foam that generates CO<sub>2</sub> <em>via</em> a reaction between potassium bicarbonate (PB) and citric acid (CA) without the aid of an external device. An anti-TNF-α antibody fragment (Fab) was loaded into the foam formulation, which promoted prolonged colon retention and improved Fab distribution up to proximal colon following rectal administration to mice. In addition, we observed increased plasma Fab concentrations in mice receiving the rectal Fab foam compared to a Fab solution. In a non-everted rat gut <em>ex vivo</em> model, a single exposure to the CO<sub>2</sub>-containing foam improved macromolecule transepithelial flux across colonic tissue by over ten-fold. Foam efficacy for Fab was investigated in a range of colitis mouse models, from acute to chronic. This non-invasive formulation platform demonstrates potential to overcome existing limitations in delivering biologics to inflamed colonic tissue.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0168365924005625/pdfft?md5=dc60066f7f941959bbc1d801a0e2e3ca&pid=1-s2.0-S0168365924005625-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors in delivering mRNA and siRNA, offering protection against enzymatic degradation, enabling targeted delivery and cellular uptake, and facilitating RNA cargo release into the cytosol. This review discusses the development and optimization of organ- and cell-specific LNPs, focusing on their design, mechanisms of action, and therapeutic applications. We explore innovations such as DNA/RNA barcoding, which facilitates high-throughput screening and precise adjustments in formulations. We address major challenges, including improving endosomal escape, minimizing off-target effects, and enhancing delivery efficiencies. Notable clinical trials and recent FDA approvals illustrate the practical applications and future potential of LNP-based RNA therapies. Our findings suggest that while considerable progress has been made, continued research is essential to resolve existing limitations and bridge the gap between pre-clinical and clinical evaluation of the safety and efficacy of RNA therapeutics. This review highlights the dynamic progress in LNP research. It outlines a roadmap for future advancements in RNA-based precision medicine.
{"title":"Enhancing RNA-lipid nanoparticle delivery: Organ- and cell-specificity and barcoding strategies.","authors":"Pu-Sheng Wei, Nagasri Thota, Gresham John, Evelyn Chang, Sunjae Lee, Yuanjun Wang, Zitao Ma, Yu-Husan Tsai, Kuo-Ching Mei","doi":"10.1016/j.jconrel.2024.08.030","DOIUrl":"https://doi.org/10.1016/j.jconrel.2024.08.030","url":null,"abstract":"<p><p>Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors in delivering mRNA and siRNA, offering protection against enzymatic degradation, enabling targeted delivery and cellular uptake, and facilitating RNA cargo release into the cytosol. This review discusses the development and optimization of organ- and cell-specific LNPs, focusing on their design, mechanisms of action, and therapeutic applications. We explore innovations such as DNA/RNA barcoding, which facilitates high-throughput screening and precise adjustments in formulations. We address major challenges, including improving endosomal escape, minimizing off-target effects, and enhancing delivery efficiencies. Notable clinical trials and recent FDA approvals illustrate the practical applications and future potential of LNP-based RNA therapies. Our findings suggest that while considerable progress has been made, continued research is essential to resolve existing limitations and bridge the gap between pre-clinical and clinical evaluation of the safety and efficacy of RNA therapeutics. This review highlights the dynamic progress in LNP research. It outlines a roadmap for future advancements in RNA-based precision medicine.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1016/j.jconrel.2024.08.020
Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.
胰腺导管腺癌(PDAC)生存率低,治疗方案有限。同期化放疗被认为有利于提高肿瘤控制率,但由于肿瘤部位的药物生物利用度低以及周围健康器官的辐射耐受性低,大大限制了其有效性。经动脉化疗栓塞术中使用的天然药物载体 Lipiodol 因其高 Z 元素碘成分而具有放射增敏剂的潜力。因此,本研究旨在重新利用脂碘作为增敏剂,同时加强对 PDAC 的化疗和放疗。为此,我们使用临床认可的表面活性剂设计了一种负载吉西他滨的稳定的脂碘乳剂(IOE)。在体内,IOE 比现有的纳米放射增敏剂具有更好的放射治疗效果,而且比游离药物具有更高的药物生物利用度,从而在同时进行化疗和放疗的情况下显著抑制肿瘤并提高生存率。这可能得益于 IOE 在 PDAC 实体瘤中的持续药物释放、均匀空间分布和长期滞留能力。此外,为了更好地了解药物负载 IOE 的作用机制,还进行了体外研究,以揭示与 ROS 和 DNA 损伤相关的治疗途径。最后,全面的毒性评估也证明了制备的 IOE 具有良好的生物相容性和安全性。这项研究为同步放化疗提供了一种临床上可行的增敏剂,并为临床上其他类型的癌症治疗提供了潜力。
{"title":"Lipiodol emulsion as a dual chemoradiation-sensitizer for pancreatic cancer treatment","authors":"","doi":"10.1016/j.jconrel.2024.08.020","DOIUrl":"10.1016/j.jconrel.2024.08.020","url":null,"abstract":"<div><p>Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1016/j.jconrel.2024.08.013
The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.
{"title":"Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor","authors":"","doi":"10.1016/j.jconrel.2024.08.013","DOIUrl":"10.1016/j.jconrel.2024.08.013","url":null,"abstract":"<div><p>The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG<sub>8</sub> linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. <em>In vitro</em> and <em>in vivo</em> results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}