Advanced Therapeutics最新文献

Doxorubicin (Dox) is a cornerstone chemotherapeutic agent for treating triple-negative breast cancer, but its clinical utility is limited by cardiotoxicity. While oral administration can circumvent the toxicity risks of intravenous delivery by enabling gradual pharmacokinetics (PK), controlled systemic exposure, and reduced toxicity peaks, Dox faces critical barriers to gastrointestinal (GI) absorption, including poor intestinal permeability, extensive hepatic first-pass metabolism, and inherent GI toxicity. To address these challenges, an orally deliverable lipid nanoparticle (Dox-LP) encapsulating a Dox-sodium taurodeoxycholate complex, engineered to enhance bioavailability while mitigating cardiotoxicity and GI damage, is developed. This study demonstrates that Dox-LP leverages dual absorption pathways, lymphatic and venous, to achieve prolonged systemic retention and enhanced tumor accumulation. This optimized PK profile significantly reduces systemic toxicity compared to intravenous Dox. Notably, Dox-LP exerts potent antitumor efficacy via a dual mechanism: direct induction of DNA damage and immunogenic cell death (ICD). ICD activation triggers robust antitumor immunity, characterized by dendritic cell maturation, expansion of cytotoxic CD8⁺ T cells, and suppression of immunosuppressive regulatory T cells (T_reg cells) and myeloid-derived suppressor cells. Collectively, the Dox-LP platform represents a novel therapeutic strategy for TNBC, synergizing enhanced efficacy with reduced toxicity through tailored oral delivery and immune modulation.

Late-stage diabetes is a complex disease caused by the interaction of the endocrine, immune, metabolic, and other systems. Currently, the clinical treatment of late-stage diabetes and its severe complications, such as diabetic nephropathy, faces numerous challenges. This study aims to compare the effects of mannose and human umbilical cord mesenchymal stem cells (UCMSC) in the treatment of late-stage diabetes, to clarify their respective advantages and applicable scopes, and to provide a scientific basis for optimizing clinical treatment protocols. The db/db mouse model at 12 weeks of age is employed, administering 8-week treatments of 20% (w v⁻¹) mannose solution and UCMSC injections, respectively. It is discovered that mannose not only significantly ameliorate glucose metabolism disorders but also markedly attenuates renal injury in late-stage diabetic mice. Importantly, compared with UCMSC, mannose exhibits more pronounced effects in improving glucose metabolism and reducing renal damage. In terms of potential mechanisms, mannose is more effective than UCMSC in inhibiting the specific pro-inflammatory cytokine, interleukin-1β. In summary, compared with UCMSC, mannose demonstrates significant superiority in multiple key indicators for the treatment of late-stage diabetes and the related nephrology. These findings offer a highly promising strategy for overcoming intractable systemic diseases, holding important clinical and research value.

Interpenetrating polymeric network microparticulate system (IPN MPs) consisting of marine polysaccharides, Fucoidan and Laminarin, was developed using the emulsion cross-linking method. The formation of the IPN MPs was confirmed by Fourier transform infrared spectroscopy (FTIR), solid state nuclear magnetic resonance (ssNMR), differential scanning calorimetry (DSC), thermal gravimetric analysis TGA), and X-ray diffraction (XRD) analyses. The effect of varying IPN blend composition on the internal aqueous phase viscosity, particle size, drying rate, matrix topography, and swelling index of the IPN MPs matrix was investigated thoroughly. In vitro degradation studies demonstrated a tunable degradation profile with less than 2% weight loss over two weeks. Evaluation of biointeraction and irritancy potential revealed a hemolysis rate below 5% and an irritation score of 0, demonstrating their non-hemolytic and non-irritant behaviour. Further, evaluation of cytotoxicity including immuno and skin compatibility, via MTT and live/dead assays validated their safety profile. Moreover, a promigratory effect greater than 70% was reported in an in vitro model of skin wounds. Further, ex vivo bioadhesion study revealed good adhesion to biological tissues. These findings confirm that the IPN MPs matrix is a promising candidate for advanced therapeutic applications targeting the skin, particularly in wound healing, and pave the way for future drug delivery investigations.

Collagen plays a critical role in wound repair. Current recombinant collagen therapies provide exogenous collagen to the wound site; however, they fail to stimulate endogenous collagen production, which is crucial for achieving structurally integrated and durable tissue repair. To overcome this critical limitation, ionizable lipid nanoparticles (LNPs) are engineered containing nucleotide-modified messenger RNA (mRNA) that encodes collagen. In immortalized human keratinocytes, these mRNA-LNPs successfully expressed collagen. Functional assays of the mRNA-LNP-treated keratinocytes revealed cell migration rates tripled, superoxide dismutase activity increased by 40%, and proliferation is slightly enhanced. In mice, subcutaneous delivery of luciferase mRNA-LNP showed rapid fluorescence generation (4 h postinjection) with sustained expression up to 144 h. In an 8-mm full-thickness wound model, collagen mRNA-LNP-treated tissue saw a wound area reduction of 40% at day 3 compared with 10% reduction in the control. A histological evaluation demonstrated a significant increase in neovascularization density and higher collagen depositioncompared to the control. These findings demonstrate that collagen mRNA-LNPs accelerated wound healing through coordinated mechanisms that enhanced cell migration, oxidative stress resistance, angiogenesis, and extracellular matrix remodeling. The technology overcomes limitations of existing collagen-based therapies by enabling endogenous protein biosynthesis, offering translational potential for dermatological applications.

Precision diagnosis and treatment of cancer are challenged by insufficient sensitivity and the absence of multi-modal collaborative therapies. Organic fluorescent probes, with their tunable optical properties and multifunctional integration capabilities, offer innovative solutions for integrated cancer diagnosis and therapy. Here, the functional principles and optimization strategies for multimodal diagnosis and treatment are systematically elucidated, revealing the core mechanisms that reconcile the inherent conflict between imaging and therapeutic functionalities through light-regulation processes. This review comprehensively discusses cutting-edge strategies for the design and application of organic fluorescent probes, systematically outlining molecular design approaches and functional integration applications. The characteristics and optimization directions of traditional fluorescent probes and novel AIEgens are critically examined, while also highlighting the unique advantages of metal-coupled probes and conjugated oligo-electrolytes. In summary, a comprehensive overview of the functional integration and molecular design of organic fluorescent probes for cancer optical diagnosis and treatment is provided, aiming to advance the development and evolution of next-generation cancer diagnostic and therapeutic tools.

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, faces limited treatment options due to the absence of hormone receptors and frequent resistance to current therapies. This highlights the urgent need to uncover novel therapeutic targets and treatment strategies to address its progression. In this study, an integrated computational and experimental approach identified maternal embryonic leucine zipper kinase (MELK) as a consistently overexpressed oncogenic driver in TNBC, regulating cell cycle and survival pathways. To target MELK, a high-throughput molecular simulation-based drug repurposing screen of FDA-approved drugs identified Netarsudil and Dutasteride as top candidates, exhibiting high binding affinities (−121.34 and −107.09 kJ mol⁻¹, respectively). Experimental validation in MDA-MB-231 and MDA-MB-468 TNBC cells demonstrate that both drugs effectively suppressed their proliferation and migration abilities. Additionally, they modulated MELK-associated pathways, inducing 1.5–3-fold changes in cyclins, p21, p53, and survivin expression. Mechanistically, the drugs effectively inhibit the role of MELK in mitotic progression and apoptosis evasion, evidenced by elevated reactive oxygen species (ROS), nuclear morphological alterations, and significant S-phase cell cycle arrest. These findings position MELK as a promising therapeutic target and highlight the potential of repurposed drugs to influence oncogenic processes in TNBC cells, offering a novel targeted therapy for TNBC.

The Omicron variants of SARS-CoV-2 are characterized by their high transmissibility and immune evasion. Existing treatments using neutralizing antibodies have shown different effectiveness due to variants with mutations occurring mainly in the RBD and NTD regions. In this study, the functional neutralizing ability of a camelid full-length antibody (hcAb-B10) and its corresponding VHH fragment (VHH-B10) is investigated. Experimental binding studies demonstrated clear recognition and neutralization of Wild-type (WT) and Omicron variants, but not Delta. Epitope mapping, peptide fragment inhibition, and neutralization studies using pseudovirus expressing respective SARS-CoV-2 Spike variants, along with in silico molecular docking studies and AI-directed structural design, reveal that the B10 antibody interacts effectively with the Spike trimer in a closed position of both WT and Omicron, by targeting the RBD region. This newly generated B10 antibody shows a wide coverage, including the currently dominant Omicron variants, and demonstrates its potential to efficiently neutralize SARS-CoV-2.

The present study introduces a novel poly(N-isopropylacrylamide)-collagen type II (PNiPAAm+CII) monolithic sub-freezing gel column, designed to specifically capture CII-specific autoantibodies directly from whole blood in a collagen-induced arthritis (CIA) mouse model. Synthesized using a sub-freezing gelation, the PNiPAAm+CII gel displayed a highly interconnected porous structure with micron-sized pores (81–237 µm), allowing the smooth serum flow and cells passage. Mechanical testing showed good structural integrity, with a significantly higher elastic Young's modulus (Y = 2291.3 psi) than the control PNiPAAm gel (Y = 385.1 psi). Biocompatibility confirmed through the MTT assay, demonstrating good cytocompatibility. Hemocompatibility test showed negligible hemolysis for the PNiPAAm+CII gel (0.02%), significantly lower than the control PNiPAAm gel (84%). Additionally, the PNiPAAm+CII gel retained low binding of blood cells after incubation with whole blood. Anti-inflammatory analysis showed no significant production of reactive oxygen species, upon cell contact. Notably, the PNiPAAm+CII gel demonstrated a strong biological affinity for CII-specific autoantibodies, capturing 15.4 U mL⁻¹ from CIA mouse serum. Remarkably, it selectively captured 24.5 U mL⁻¹ of CII-specific autoantibodies from whole blood without the need for pre-processing. The PNiPAAm+CII gel offers a promising approach for the selective depletion of antigen-specific IgG, potentially future management of autoimmune arthritis.

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

T-cells forced through micro-sized pores become permeable, letting Chimeric Antigen Receptor (CAR) mRNA enter. The cells then express CAR proteins, gaining potent cancer-killing function. This method offers a path toward efficient, reproducible manufacturing and reduced therapy costs for patients. More details can be found in the Research Article by Cyrus W. Beh and co-workers (DOI: 2500094). Cover image by Ahmad Amirul Abdul Rahim.