Advanced Therapeutics最新文献

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

Metastasis drives treatment failure and cancer mortality, yet preclinical studies still rely heavily on subcutaneous xenograft models that prioritize tumor growth over metastatic biology. This disconnection from clinical reality significantly contributes to the high failure rate of experimental therapies in trials. Here, current mechanistic insights is integrated into metastasis and critically assess transplantation models to inform rational model selection for metastasis research. Tumor transplantation models exhibit distinct dissemination patterns governed by implantation methodology rather than intrinsic tumor properties. Subcutaneous models, while technically accessible, predominantly assess primary tumor growth and fail to capture critical metastatic steps like intravasation, pre-metastatic niche formation, and organotropism. Orthotopic transplantation faithfully replicates native tissue microenvironments, enabling simultaneous assessment of tumor growth and metastatic potential. Intravascular models, while inducing rapid colonization, distort natural metastatic progression by skipping early dissemination stages. Metastatic site transplantation isolates microenvironmental impacts on tumor adaptation but fails to capture de novo metastatic initiation. Ultimately, three strategies is proposed for preventing metastasis: Eradicating circulating tumor cells, blocking colonization, and stifling outgrowth. This perspective catalyzes the strategic advancement of tumor metastasis models, thereby strengthening the reliability of preclinical findings and accelerating their clinical translation.

Lupus nephritis is a serious complication of childhood systemic lupus erythematous (cSLE). Nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation is one of the pathogenic pathways leading to deterioration of kidney functions in cSLE causing end stage kidney diseases (ESKD). Curcumin as a potent anti-oxidant, anti-inflammatory and nephroprotective drug has proved experimentally its benefits on murine lupus via inhibiting NLRP3 inflammasome. This study aimed to investigate the effects of curcumin supplementation in pediatric patients with active lupus nephritis. In this randomized controlled trial, 44 patients with lupus nephritis are randomized to receive either curcumin tablets (1000 mg curcumin) added to their standard immunotherapy for 12 weeks, or their standard immunotherapy alone. Serum NLRP3 inflammasome, complement component 3 (C3), 24-h urine protein and erythrocytes sedimentation rate (ESR) are measured at baseline and after 12 weeks. A total of 44 patients with a mean age of 13.3 ± 4.7 years completed the trial. Curcumin- supplementation for 12 weeks resulted in significant reduction in serum NLRP3 inflammasome and improved complement component 3 (C₃) with p-values (0.0399) and (<0.0001) respectively, compared to patients on the standard immunotherapy alone. Curcumin is an effective add-on anti-inflammatory agent in childhood lupus nephritis.

Effective pain management, particularly following physical injury, remains a major clinical challenge due to the limitations of systemic analgesics, including opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), which often cause adverse effects and provide inadequate site-specific relief. Emerging strategies that utilize nanoparticles and gene therapy offer promising alternatives by enabling localized delivery of analgesic agents directly to injured tissues. Nanocarriers such as liposomes, polymeric nanoparticles, and gold-based systems facilitate targeted accumulation and controlled release of therapeutic agents, thereby enhancing efficacy while reducing systemic toxicity. Concurrently, gene therapy enables modulation of pain-associated pathways through tissue-specific expression or silencing of target genes, offering sustained and potentially long-term analgesia. This review discusses the mechanisms, design principles, and recent advances in nanoparticle- and gene therapy-based approaches for pain modulation. Preclinical models and early clinical investigations indicate the feasibility of these technologies in achieving targeted, prolonged pain relief. Key barriers to clinical translation, including delivery efficiency, immune compatibility, and regulatory considerations, are also addressed. Future directions highlight the integration of responsive nanomaterials, CRISPR-based gene editing, and hybrid platforms as next-generation solutions for personalized, site-specific pain management.

Bioengineered allogeneic cellularized constructs (BACC) promote wound closure in deep partial thickness burns, but the mechanisms behind these effects are poorly understood. In normal wound healing, phagocytosis of cells by macrophages is a potent mechanism by which pro-healing macrophage phenotypes form. The purpose of this study is to determine if macrophages are capable of phagocytosing BACC-derived cells and whether this process affects macrophage phenotypes. Primary human macrophages from 21 healthy donors are cultured on BACC constructs over 6 days in vitro. Phagocytosis is analyzed by confocal imaging, timelapse imaging, multidimensional flow cytometry, and imaging flow cytometry. Macrophages phagocytosed BACC-derived cells, although the number of macrophages that internalized BACC-derived cells varied depending on the method of analysis. Inhibitors of efferocytosis and phagocytosis suppressed macrophage uptake of BACC cells and markers of reparative phenotypes, including CD206 and CD209, as well as the pro-inflammatory marker CD38. These results demonstrate that macrophage phenotype changes in response to BACC are at least partially due to the phagocytosis of cells within the BACC. These findings provide important insight into how engineered tissues may influence macrophage phenotype to promote tissue repair.

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.