Advanced Therapeutics最新文献

Osteosarcoma is an aggressive pediatric, adolescent, and young adult bone cancer with an immunosuppressive tumor microenvironment (TME) that limits immunotherapy efficacy. Tumor-associated macrophages, key players in immunosuppression and metastasis, are abundant in the osteosarcoma TME. The cGAS/STING pathway has emerged as a target for enhancing anti-tumor immunity. Here, this work investigates whether STING stimulation could reprogramme macrophages toward a tumoricidal M1-like phenotype and enhance doxorubicin efficacy against osteosarcoma. These results show that while doxorubicin induces cell death of osteosarcoma cells, it fails to activate STING in macrophages. However, pre-treatment of macrophages with a STING agonist enhances M1-like polarization of macrophages when indirectly co-cultured with chemotherapy-treated osteosarcoma cells, regardless of the original macrophage phenotype. Importantly, this work observes a loss of STING protein when cells are excessively stimulated with a STING agonist and sequential dosing offered no advantage over a single treatment. Finally, this work demonstrates that the combined therapy of doxorubicin and a single dose of neoadjuvant STING agonist synergistically increases osteosarcoma cell death via M1-macrophages compared to either therapy alone. These findings highlight the therapeutic potential of STING agonists to reprogram macrophages within the TME, and improve chemotherapy efficacy, offering a promising new strategy to enhance osteosarcoma treatment options.

The success of medical devices and biomaterials hinges on selecting biological models that truly reflect human physiology and disease. A well-chosen model is not just a scientific necessity; it is a clinical imperative. Academic biomedical research often relies on readily accessible models that yield affordable, convenient, and predictable results. However, rodent models of sepsis, cancer, and cardiovascular disease frequently fail in clinical translation. Likewise, optimizing a device or material to fit a specific model (“overfitting”) can create false confidence, leading to expensive setbacks. While in vitro systems offer ethical advantages and mechanistic insights, they lack the complexity of living organisms. Animal models, though capable of capturing systemic effects, face species differences, ethical concerns, and poor clinical translation. Advances in 3D tissue engineering, organ-on-a-chip, and humanized models overcome many of these shortcomings, improving predictive accuracy and complementing animal models. Clinician involvement is crucial to aligning preclinical models with real-world medical needs. Moreover, unnecessary animal experiments should not be conducted or required without a clear translational route. Prioritizing clinically relevant models enhances patient safety, reduces research waste, and drives ethical, impactful medical innovation.

Hyperglycemia aggravates neuronal damage in cerebral ischemia/reperfusion (I/R) injury. Emerging evidence indicates that Lycium barbarum polysaccharides (LBP) possess significant neuroprotective properties. However, the underlying mechanism by which LBP alleviates hyperglycemia-aggravated cerebral I/R injury remains unclear. This study aims to investigate the effects of LBP on hyperglycemia-aggravated cerebral I/R injury using in vivo and in vitro models. Rats are randomly assigned to the following groups: normoglycemic (NG), hyperglycemic (HG), and LBP-pretreated hyperglycemic (LBP) groups. Streptozotocin‑induced hyperglycemic rats undergo middle cerebral artery occlusion (MCAO) for 30 min, followed by reperfusion for 1, 3, and 7 days. Meanwhile, an in vitro model of hyperglycemia-aggravated cerebral I/R injury is established using murine hippocampal neuronal HT22 cells subjected to high glucose (HG) conditions combined with oxygen deprivation and reoxygenation (OD). The results demonstrate that compared to the NG group, the HG group exhibits significantly increased neurological deficit and larger infarct area. Pre-treatment with LBP significantly attenuates these hyperglycemia-aggravated neurological deficits and reduces the infarct area. Furthermore, LBP treatment elevates the cell viability of HT22 cells in the HG and OD groups. Additionally, LBP significantly alleviates the hyperglycemia-induced downregulation of β-catenin and p-GSK-3β expression both in vivo and in vitro. These results demonstrate that LBP alleviates hyperglycemia-aggravated cerebral I/R injury by upregulating the Wnt/β-catenin signaling pathway.

Current treatments for cancer such as surgery, chemotherapy, radiotherapy, and chemodynamic therapy often exhibit poor efficacy and severe side effects; this, cancer remains a major global health challenge. In the ongoing exploration of therapeutic strategies with improved outcomes and reduced adverse effects, phototherapies (PTs), including photothermal (PTT) and photodynamic therapy (PDT), are gaining attention due to their non-invasive and targeted nature, resulting in reduced side effects. However, further material optimizations are needed to enhance PT performance. Metal-organic frameworks (MOFs) have emerged as promising PTT/PDT nanoplatforms due to their tunable structures, high surface area, and ability to host photoactive agents. Their porous architecture facilitates efficient photosensitizer encapsulation and promotes light-induced thermal effects, improving therapeutic stability and efficacy. The therapeutic potential of MOFs is further enhanced when combined with multiple treatment modalities. This review focuses on the roles of Fe/Cu-based MOFs in PTs, their synthesis, underlying mechanisms in PTT/PDT, and recent design advancements. It also summarizes the progress in Cu/Fe-MOF nanocomposite development over the past 5 years, from construction to synergistic applications. These insights can inform future efforts in the clinical translation of Cu/Fe-MOFs in cancer theranostics.

Photodynamic therapy (PDT) is a clinically approved anticancer treatment based on the generation of reactive oxygen species (ROS) when a photosensitizing agent (PS) is irradiated with specific light. Typically, irradiation is performed to cover the entire tumor or treatment area. However, this approach presents some disadvantages, including irradiation of the surrounding normal tissue. Therefore, this study introduces a novel phototherapeutic approach using single-point laser irradiation. With the plasma membrane as the primary organelle target, it is demonstrated that single-point laser irradiation induces plasma membrane damage in cancer cells using two clinically approved fluorescent markers for Glioblastoma: Protoporphyrin IX (PPIX), which localizes to the plasma membrane, and Sodium Fluorescein (NaF), which remains in the extracellular space, contacting the membrane. Single-point laser irradiation in photodynamic therapy induces plasma membrane disruption in both cases, resulting in selective necrotic cancer cell death. Interestingly, this approach induces cell death from within the spheroids, and the cell death gradually extends to the rest of the spheroid, minimizing damage to the surrounding tissue. In conclusion, this study presents a novel approach using focused laser irradiation and clinically approved dyes to induce precise, targeted cell death within the tumor, suggesting potential for theranostic applications in tumor eradication.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a need for more effective and less invasive treatment options. This study aimed to develop a targeted drug delivery system using hyperbranched polyglycidylglycerol-poly(lactic acid)-hydroxyacetic acid (HPG-PLGA)nanoparticles (NPs) loaded with baicalin (BN), a flavonoid with potent anti-inflammatory properties, to enhance therapeutic efficacy in UC. HPG-PLGA NPs are synthesized, characterized, and loaded with BN. The particle size, polydispersity index (PDI), encapsulation efficiency, and in vitro release profile of the NPs are evaluated. The in vivo biodistribution and therapeutic efficacy of the NPs are assessed in a dextran sulfate sodium-induced UC mouse model. The synthesized HPG-PLGA NPs demonstrated good stability and a controlled release of BN. In vivo studies showed significant accumulation of NPs in the inflamed colon, with a subsequent reduction in disease activity and inflammation markers. The treatment group exhibited lower levels of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 compared to the model group, indicating effective alleviation of inflammation. Furthermore, the NPs showed no significant toxicity to major organs. This study provides a promising approach for the development of targeted UC treatments, offering a potential clinical application by enhancing the bioavailability and specificity of BN to inflammatory sites.

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

Ultraviolet (UV) photocurable bisphenol A-glycerolate dimethacrylate (bis-GMA) and pentaerythritol tetrakis(3-mercaptopropionate) (PETMP)-based copolymers have been synthesized usingthiol-ene chemistry with tailorable size. This copolymer was further grafted with polyurethane (PU) through in-situ polymerization using its diisocyanate chain ends to balance its hydrophobicity for controlled drug delivery. Characterization by various spectroscopic techniques confirmed the structure, shape, and size of the synthesized polymer; thermal analysis revealed higher glass transition temperatures, and enhanced thermal stability. Rheological analysis showed improved strength and favourable flow behaviour. UV–Vis and FTIR demonstrated strong polymer–drug interactions, correlating with the sustained drug release observed, in contrast to pure PU and copolymer. Drug-loaded graft copolymer was incorporated into 3D-printed scaffolds, supporting in vitro cell growth for 7 days, confirming biocompatibility. An in vivo melanoma mouse model study showed considerable tumor reduction without any side effects, unlike traditional chemotherapy, owing to localized hydrogel injection beneath the tumor for sustained release. Overall, this injectable hydrogel, derived from the synthesized graft copolymer, offers a thermally stable, mechanically robust, biocompatible, and a viable drug delivery system for cancer therapy, with reduced toxicity and high therapeutic potential.

Circulating tumor cells (CTCs) are seeds for metastasis and are key elements of liquid biopsies. Despite their small numbers, CTCs exhibit significant heterogeneity in terms of quantity, surface markers, and physical characteristics. This diversity poses challenges for the accurate detection and analysis of CTCs, which are essential for precise diagnosis and clinical decision-making. Additionally, spatiotemporal changes in physiological systems and the presence of circulating tumor endothelial cells (CTECs) contribute to fluctuations in the numbers and properties of both individual and clustered CTCs, affecting molecular changes and metastatic potential. It is imperative to carefully consider these variations during blood sampling, CTC detection, result analysis, and treatment planning to ensure successful clinical outcomes. The review has explored various aspects of CTC heterogeneity, emphasizing additional factors that may impact the reliability of CTC analyses and their clinical relevance for patient care. Furthermore, insights are offered to enhance the understanding of CTC heterogeneity in the context of precision diagnosis and clinical management.

In recent years, cellular immunotherapies, such as chimeric antigen receptor T (CAR-T) therapy, have emerged as promising treatment options for cancer, demonstrating particularly strong efficacy against liquid tumors. By introducing tumor-targeting CAR genes into patient immune cells ex vivo and reintroducing the modified cells into the patient, tumor cells expressing specific surface markers can be selectively killed. However, existing virus-based methods for producing cellular products are plagued by high costs, which seriously limit their adoption. In this paper, the development of a mechanical transfection device is described, which passes cells through micron-sized pores and is capable of delivering different molecules into cells. The effects of parameters such as pore size, flow rate, and payload concentration on transfection efficiency are studied and used to inform a standard transfection protocol. Finally, the delivery of CAR-encoding mRNA into primary T-cells is demonstrated to manufacture CAR-T cells, which secrete IFN-γ and TNF-α in an antigen-specific manner. As the method is developed from the outset to be easily deployable and scalable, it is envisioned that it will be able to impact cell manufacturing in the near future.