Advanced Therapeutics最新文献

Radiotherapy (RT) is one of the widely used cancer treatments, but its efficacy can be limited by the hypoxic tumor microenvironment (TME), which reduces reactive oxygen species (ROS) generation and promotes radioresistance. Recent studies suggest that gas small molecule-mediated sensitization may be a promising strategy for enhancing radiosensitivity. Therapeutic gas small molecules, including nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S), ozone (O₃), hydrogen (H₂), and sulfur dioxide (SO₂), have demonstrated potential in regulating the TME. These gas small molecules have been shown to improve tumor oxygenation, promote ROS generation, induce DNA damage, and modulate immune responses, which may contribute to enhanced RT outcomes. This review summarizes the latest progress in gas small molecule-mediated radiosensitization strategies, focusing on the release mechanisms, therapeutic platforms, and potential clinical applications. Additionally, current challenges and future directions in this field are discussed, aiming to provide insights into optimizing the gas small molecule-mediated radiosensitization strategy.

Smart stimuli-responsive nanomaterials have emerged as promising candidates in pharmaceutical delivery due to their ability to react to diverse physical, chemical, and biological stimuli. These systems can be precisely engineered to release therapeutic agents in response to specific internal cues, allowing for controlled and targeted interventions tailored to individual patient conditions. Their nanoscale architecture, ease of surface modification, and multifunctional physicochemical properties further enhance their suitability for biomedical applications. Recent advances underscore their potential in treating complex and chronic diseases such as cancer, neurological disorders, and inflammatory conditions, where conventional therapies often fall short. By integrating these responsive nanotechnologies into precision medicine, it is possible to enhance therapeutic efficacy while minimizing systemic toxicity. Herein, this work highlights the ongoing progress in the development and application of stimuli-responsive nanomedicines. This work also emphasizes the need for extensive clinical validation to determine their long-term safety and effectiveness in human subjects.

Despite renewed interest in IL-12 as a cancer immunotherapy due to its ability to stimulate the adaptive immune system, its short half-life and narrow therapeutic window continues to present challenges for effective delivery. Previous studies with IL-12 have investigated the effects of route of delivery or sustained delivery of the cytokine on its efficacy but are unable to simultaneously investigate the effects of both within the same system. This work seeks to address this gap by utilizing an elastin-like polypeptide (ELP) carrier, which can undergo a thermally triggered phase transition to a gel-like depot, to probe the effects of both sustained release and spatial delivery of IL-12. By conjugating IL-12 with an ELP, this work creates an IL-12-ELP fusion that can be injected intratumorally or subcutaneously to form a sustained-release depot. In a B16F10 murine model, intratumoral injection of a depot-forming IL-12-ELP fusion significantly improved survival compared to free IL-12. IL-12-ELP is retained within the tumor approximately fourfold longer than free IL-12, resulting in higher CD8+ T cell recruitment at the tumor and local concentrations of inflammatory cytokines at Day 2. Taken together, this work provides insights into rational cytokine delivery, the importance of tumor localization, and the benefits of sustained release.

During pregnancy, the maternal immune system adapts to balance tolerance of the semi-allogenic fetus while protecting the fetus from pathogens. Dysregulated immune activity at the maternal–fetal interface contributes to pregnancy complications, such as recurrent pregnancy loss and preeclampsia. Compared to healthy placentas, preeclamptic placentas exhibit increased pro-inflammatory signaling, including a predominance of inflammatory macrophages, leading to impaired tissue remodeling and restricted blood flow. However, the precise mechanisms driving this immune imbalance remain poorly understood, in part due to the lack of tools to probe individual pathways. Here, lipid nanoparticles (LNPs) are used to deliver cytokine-encoded mRNA to placental cells, called trophoblasts, enabling local immunomodulation. LNP-mediated delivery of IL-4 and IL-13 mRNA induced cytokine secretion by trophoblasts, leading to polarization of primary human monocytes toward anti-inflammatory phenotypes. Notably, lowering the mRNA dose increased expression of alternatively-activated macrophage markers, revealing an inverse relationship between dose and polarization status. Intravenous injection of LNPs in pregnant mice achieves placental secretion of IL-4 and IL-13 with minimal changes to pro-inflammatory cytokines in the serum. These findings establish LNPs as tools for local immunomodulation in the placenta, offering a strategy to study and treat immune dysfunction in pregnancy and in other inflammatory conditions.

Liquiritin, a flavonoid from Glycyrrhiza uralensis L., has diverse pharmacological properties, but its impact on fracture healing is unexplored. This study investigates its osteogenic and antioxidative effects on bone marrow mesenchymal stem cells (BMSCs) in vitro and its regenerative effect on rat femoral fractures in vivo. Cytotoxicity is assessed via MTT assay, and osteogenic differentiation via ALP and ARS staining. A rat femoral fracture model validates its therapeutic effects, with micro-CT and histological assessments evaluating healing outcomes. Gene and protein expression in osteogenic and signaling pathways are analyzed through RT-qPCR, western blot, and immunofluorescence. ROS levels are measured using DCFH-DA staining. Results show liquiritin enhances osteogenesis in BMSCs, evidenced by increased ALP activity and calcium deposition. In rats, it facilitates bone regeneration and upregulates phosphorylated ERK and JNK. Additionally, it reduces ROS generation post-oxidative injury, boosting NRF2, HO1, and NQO1 expression.

The clinical translation of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) holds immense promise due to their regenerative and immunomodulatory properties. However, their widespread application is hindered by challenges in storage, stability, and cold chain transport. In this study, it is explored lyophilisation as a strategy to extend the shelf life of MSC-sEV while maintaining their structural integrity and biological functionality. Lyophilised sEV are stored at four different temperatures—room temperature (RT), 4, −20°C, and −80 °C—for durations of 1, 3, and 6 months. This findings reveal that normal refrigeration temperature of 4 °C storage is suitable for maintaining sEV stability for up to 1 month, while −20°C and −80 °C are more effective for longer durations, preserving sEV integrity and functionality for 6 months and beyond. These results underscore the importance of optimizing storage protocols for lyophilised MSC-sEV to ensure their viability for clinical and research applications. This study establishes a foundation for improved storage and cold chain transport of MSC-sEV, paving the way for their integration into scalable and standardized therapeutic platforms.

Cover image provided courtesy of Yongheng Zhu, Xinghua Gao, Yuan Zhang, and co-workers.

Genetic engineering in primary T cells is gaining traction in the context of gene therapy and cell therapy, with studies aiming to either induce gene expression/correction, gene inhibition, or a combination of both. These genetic modifications can be achieved using a variety of methods, each with its own advantages and limitations. Also, primary T cell genomes can be edited stably, leading to permanent changes, via methods such as lentiviral transduction and CRISPR; and they can also be edited transiently, using tools such as mRNA transfection, to induce only temporary expression or inhibition of genes. While each of these methods possesses their own characteristics that distinguish them from each other, they also face obstacles in their usage in primary T cells. In this review, the principles and mechanisms behind these gene manipulation tools, as well as their advantages and potential limitations, are discussed.

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular condition with complex pathophysiology, for which effective pharmacological treatments are currently lacking. Recently, ferroptosis has been identified as a key mechanism of vascular smooth muscle cell (VSMC) death, emerging as a potential therapeutic target for mitigating aortic aneurysms. Here, a drug-delivery nanoparticle system combining tea polyphenol-based nanoparticles and a ferroptosis inhibitor is developed. This system, formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates Ferrostatin-1 (Fer-1) during self-assembly and is subsequently functionalized with fibronectin (FN) for targeted treatment of angiotensin II-induced AAA. Both in vitro and in vivo experiments demonstrated that TPN-Fer-1@FN effectively inhibits ferroptosis, suppresses the inflammatory response, and reduces matrix degradation, while preserving the normal contractile function of VSMCs and modulating the NOTCH3 signaling pathway. Moreover, the TPN-Fer-1@FN nanosystem exhibited low toxicity and good biocompatibility. These findings suggest that TPN-Fer-1@FN represents a promising therapeutic strategy for inhibiting ferroptosis and modulating the pathological processes underlying AAA.

Sono-photodynamic therapy (SPDT), a useful technique applied in combination with photodynamic therapy (PDT) and sonodynamic therapy (SDT), reduces potential side effects compared to monotherapy. This study reports the photochemical and sono-photochemical properties and in vitro analysis of silicon (IV) phthalocyanine (SiPc), with a particular focus on its efficiency in singlet oxygen production. When photochemical investigations are conducted alone, the SiPc Φ_∆ value is measured as 0.68; however, when light and ultrasound are combined, the value increased by 25% to 0.85 in sono-photochemical studies. The Q-band of the calculated SiPc UV–vis spectrum is found to be in very good agreement with the experimental data, with the computed oscillator strengths (the absorption intensities) for Q-band being higher than for B-band. Furthermore, the therapeutic effects of PDT and SPDT using SiPc are evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. The results demonstrated that SPDT, combining light and ultrasound, significantly enhanced cytotoxicity compared to PDT alone. Additionally, SPDT triggered pyroptosis, characterized by upregulation of NLRP3, CASP1, IL1B, and IL18, revealing a distinct mechanism of cell death. These findings suggest that SiPc-mediated SPDT amplifies oxidative stress and activates multiple cell death pathways, offering a promising and targeted approach for improving breast cancer therapy.