Advanced Therapeutics最新文献

Traumatic brain injury (TBI) is a complex neurological condition involving both primary mechanical damage and a cascade of secondary injuries, such as oxidative stress, neuroinflammation, and disruption of the blood-brain barrier (BBB). Although significant progress has been made in understanding TBI pathophysiology, current treatment strategies remain largely supportive and fail to effectively target the underlying secondary injury mechanisms. This therapeutic gap highlights the urgent need for innovative and more effective interventions. Nanotechnology has emerged as a promising avenue, offering targeted drug delivery systems, improved BBB penetration, and integrated diagnostic and therapeutic capabilities. These innovations have the potential to significantly enhance treatment precision and outcomes in TBI. This review provides a systematic overview of the pathological processes underlying TBI, critically assesses the limitations of existing therapeutic approaches, and summarizes recent advances in nanomedicine-based strategies developed over the past five years. Particular emphasis is placed on emerging diagnostic technologies and therapeutic innovations, offering perspectives on future directions for TBI research and clinical translation.

The multifunctional strategy offers significant benefits in developing highly selective targeting biomolecules for therapeutics, diagnostics, dynamics studies, or mapping processes in various environments. Bioorthogonal reactions constitute an engineering approach enabling the attachment of ligands targeting receptors involved in numerous physiological dysfunctions onto multifunctional scaffolds. Herein, the latest generation of derivatized probes are overviewed for high-resolution screening in diagnosis or treatment. These compounds also represent valuable tools for investigating physiological roles, filling the gap of information in the mechanism of understanding various receptors and contributing to the design of effective drugs. Strategic linker design enhances ligand properties when developing dual-modality probes, impacting their effectiveness across applications. Nanoparticles are emerging as revolutionary concepts, offering promising solutions to address limitations in the field and paving the way for advanced therapeutic approaches and improved drug delivery systems.

Silk-derived protein (SDP) is a fibroin hydrolysate that has been found to increase corneal epithelial cell migration rates in vitro and enhances corneal tissue regeneration in vivo, however, the mechanism of these bioactive effects is unclear. Previous work has shown that selecting specific molecular weight distributions (MWD) of the fibroin hydrolysate can impact its bioactivity. In this study, the effects of high (H⁻) and low molecular weight (L⁻) SDP fractions on human corneal limbal-epithelial cell viability, absorption, migration, attachment, and TGF-β signaling are characterized. Interestingly, L-SDP significantly increased cell migration and proliferation to accelerate wound closure rate, while the presence of TGFβRI inhibitor attenuated its activity. In contrast, H-SDP significantly decreased migration while increasing substrate adhesion, also down-regulating TGF-β mRNA levels. These findings demonstrate SDP's bioactivity can be tailored to govern cellular migration or adhesion by selecting a MWD which is optimal for a specific application.

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.