Advanced Therapeutics最新文献

Cytokines are central in orchestrating immune responses during tissue repair and regeneration, making them attractive candidates for regenerative medicine. However, their pleiotropic effects, short half-life, and poor biodistribution have limited their clinical translation. Advances in protein engineering have enabled the design of modified cytokines with enhanced stability, receptor selectivity, and tissue-targeting capabilities, offering new therapeutic opportunities for modulating immune activity and promoting tissue healing. Many of these engineering approaches have been pioneered in cancer immunotherapy, where cytokines are often designed to sustain inflammation and enhance cytotoxic immune responses. In contrast, regenerative medicine usually requires immune resolution, necessitating a distinct and sometimes opposite application of cytokine engineering strategies. This review explores the latest advancements in cytokine engineering for regenerative applications, focusing on strategies to enhance cytokine stability, modulate receptor affinity, improve targeting, and regulate endogenous cytokine signaling. Numerous approaches, highlighting how targeted immune modulation can enhance tissue healing while minimizing fibrosis and chronic inflammation, are discussed. These advances hold great promise for treating chronic wounds, fibrotic diseases, and tissue injuries with limited regenerative capacity, paving the way for precise, effective, and clinically translatable cytokine therapeutics. By adapting principles from cancer immunotherapy, cytokine-based therapies could transform regenerative medicine.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited response to chemotherapy and immune checkpoint inhibitors (ICIs). This study evaluates the efficacy and safety of combining Albumin-Bound Paclitaxel (nab-PTX) with an anti-PD-1 antibody and aims to identify potential biomarkers to optimize therapeutic outcomes. The murine model of PDAC is established by subcutaneously injecting the murine pancreatic cancer cell line Panc02 into C57BL/6J mice. The mice are treated with either an anti-PD-1 antibody, nab-PTX, or nab-PTX plus anti-PD-1 antibody, with untreated mice serving as the control. Tumor growth, immune cell infiltration, cytokine levels, overall survival, organ damage, and gene expression profiles are analyzed. The combination therapy shows superior efficacy compared to nab-PTX and non-inferior efficacy compared to the anti-PD-1 antibody. Moreover, this strategy significantly reduces the risk of irAEs and hyperprogression caused by the anti-PD-1 antibody. In addition, screening identifies WNT9a as a potential gene associated with improved efficacy and ATF3 with enhanced safety, providing valuable insights for optimizing therapeutic strategies in PDAC.

Photobiomodulation (PBM) has emerged as a promising therapeutic approach for modulating cellular behavior and improving health outcomes, particularly in the context of vascular health. Despite growing interest in PBM, a key gap exists in understanding how specific wavelengths, such as 680 and 850 nm, affect endothelial cell function. While light's general effects on cell viability and mitochondrial function are known, the precise mechanisms underlying PBM's influence on endothelial cells remain unclear, limiting the optimization of PBM protocols for vascular dysfunction. In this study, the effects of PBM on endothelial cells are investigated using the light peaked at 680 and 850 nm with full width at half maximum (FWHM) about 17.5 and 25.1 nm, respectively, assessing cell viability, mitochondrial activity, reactive oxygen species (ROS) production, calcium flux (Ca²⁺), and transepithelial electrical resistance (TEER). These findings demonstrate that PBM exposure enhances mitochondrial function, reduces oxidative stress, and modulates calcium signaling, all of which contribute to changes in endothelial barrier integrity. These results highlight the potential of PBM as a novel therapeutic strategy for enhancing endothelial cell function and addressing endothelial dysfunction, opening new avenues for future research and clinical applications in vascular health.

Breast cancer is one of the most prevalent solid tumors in women and can be classified into subtypes based on molecular characteristics, such as hormone receptor status and HER2 expression. Aptamers, highly specific affinity molecules, are extensively studied for targeted drug delivery using nanocarriers to enhance anti-cancer efficacy. This study focused on HER2-responsive co-delivery of doxorubicin and hyaluronidase via aptamer-gated mesoporous silica nanoparticles to improve therapeutic outcomes in solid tumors. SK-BR-3 spheroids are employed as a model for resistant tumor environments in solid tumors. Previous research is shown that conjugating cytotoxic drugs with nanoparticles or cells enhances drug penetration into tumor spheroids. In this work, doxorubicin is loaded into mesoporous silica nanoparticles and capped with HER2-specific aptamers, while the particle surface is functionalized with hyaluronidase. This dual-functionalized nanocarrier system achieves an ≈8.5-fold increase in cytotoxicity compared to aptamer-targeted delivery lacking hyaluronidase. The enhanced effect is attributed to hyaluronidase-mediated loosening of the spheroid structure, facilitating nanoparticle penetration and localized release of doxorubicin at high concentrations on HER2-positive cells.

FeS₂, a member of metal chalcogenide semiconductors, is a cheap and available material with distinguishable photothermal activity under light irradiation. However, its photodynamic properties have to be improved for practical phototherapy applications. Therefore, in this study, FeS₂/WS₂ p-n junctions, comprising varying amounts of WS₂, are synthesized using the simple hot injection method. Establishment of the heterostructure is verified using X-ray diffraction (XRD), scanning transmission electron microscopy (STEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS) analysis. p-n junction formation is further validated via calculations based on ultraviolet-visible (UV–vis.) spectrophotometer and XPS data. Photothermal and photodynamic properties of the samples are examined considering various aspects. The FeS₂/WS₂ heterostructure provides a heating response above 50 °C with a high photothermal conversion efficiency of 52.6%. The reactive oxygen species (ROS) formation ability is observed to depend on the material concentration and O₂•^‾ is determined as the primary reactive oxygen species. The in vitro antibacterial activity of the samples is tested against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria as a function of material concentration. At all concentrations, the FeS₂/WS₂ heterostructure exhibits higher activity than that of FeS₂ nanoparticles. The efficiency of the sample against S. aureus and E. coli is calculated to be 100% and 99.4% respectively, at a low material concentration of 100 µg mL⁻¹.

One of the biggest obstacles to successful cancer treatment is still therapeutic resistance, which frequently leads to recurrence and unsatisfactory clinical outcomes. MicroRNA-200c (miR-200c), one of several molecular regulators, has grown into a crucial modulator of treatment efficacy by affecting processes including apoptosis, drug efflux, epithelial-mesenchymal transition, and cancer stem cell properties. Despite extensive research on miR-200c's roles in drug resistance, there is lack of comprehensive reviews summarizing these findings. This review gathers the most recent data on the complex functions of miR-200c in mediating chemotherapy and radiotherapy resistance across various cancer types. Its potential clinical aspects as a biomarker and therapeutic target are further discussed. Finally, existing knowledge gaps are outlined, and future research directions are proposed to support development of miR-200c-based strategies for overcoming therapeutic resistance in cancer.

Increasing aging population, digital screen use, environmental factors, and sleep disorders have contributed to a rise in ophthalmic diseases. This has soared the demand for better ocular models that are more predictive and can be used to identify new pharmacological targets. Traditional models fail to recapitulate organ-level functionalities and present anatomical differences with human structures, therefore, organ-on-chip systems have emerged to tackle these limitations. Microfluidic devices is engineered to provide the layered structure that the ocular tissues require. This is combined with tight regulation of diffusion gradients and perfusion systems for toxicological analysis and drug screening applications. Incorporation of several cellular layers, motion to mimic blinking, or incorporation of ocular organoids in microfluidic devices are some of the advancements that the field has made. This work reviews the evolution of ocular microphysiological systems and discusses some challenges that could be undertaken by the organ-on-chip community.

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.