Atherosclerosis (ATS) and atherothrombosis (ATT) are among the most common cardiovascular diseases (CVDs) worldwide, with their pathological progression involving endothelial dysfunction, recruitment and activation of immune cells, gradual development of plaque, plaque rupture, and subsequent thrombosis. Over the past decade, extracellular vesicles (EVs), lipid bilayer‐enclosed particles, have been shown to play a crucial role in mediating various pathophysiological processes and facilitating intercellular communication, thereby fundamentally contributing to the physiological functions of multicellular organisms. EVs transport biological cargos, including proteins, RNA, DNA, lipids, and metabolites, which can mediate a variety of pleiotropic cellular functions. In this review, we describe EV‐mediated pathological progression of ATS and ATT. Furthermore, we outline the strategies for engineering smart EVs that specifically target componets of ATS or ATT, including injured endothelial cells, lesions, clots, or diseased regions. We also explore innovative EV‐based strategies for delivering therapeutic cargos to achieve enhanced benefits. Finally, we highlight the current challenges and future prospects of EV‐based therapeutics for ATS, ATT, and more broadly for CVDs.

Hybridization of common motifs from known antimicrobial peptides (AMPs) is a promising strategy for designing a new class of antimicrobial agents with improved activity. Herein, the machine learning-generated peptide sequence IIKLLGVLAKFVLGQ-NH2 was utilized for sequence optimization using an alanine scan and alignment with known AMPs to identify the motifs with the highest occurrences. Motifs were then assembled to obtain positively charged peptides with 12 to 18 amino acid lengths and hydrophobicity >60%. The designed peptides exhibit broad-spectrum antimicrobial activity against multiple Gram-negative and Gram-positive bacterial strains, along with excellent pH and plasma stability. The peptides demonstrate high efficiency in eradicating bacterial biofilms with no resistance development over 300 generations against a "superbug" clinical strain of Acinetobacter baumannii. Additionally, AMPs were biocompatible and promoted fibroblast migration, which accelerated artificial wound closure. This study highlights an innovative strategy for engineering highly effective AMPs with significant potential in combating multidrug-resistant pathogens.

Skeletal muscle orchestrates systemic metabolism, dynamically coordinating glucose uptake and fuel use to match energy demand. In Duchenne muscular dystrophy, loss of dystrophin derails this control, exposing a hidden metabolic weakness. In the mdx mouse, we show that physiological stress exposes a primary failure in insulin-stress axis integration: unchecked glucocorticoid signalling outpaces insulin secretion, driving systemic hyperglycaemia despite preserved muscle insulin sensitivity. These data support multi-tissue dystrophinopathy driving endocrine-metabolic decoupling. Skeletal muscle glycogen accumulates excessively and resists mobilisation under stress. The heart maintains high glucose uptake, whereas the brain remains glucose-limited, defining tissue-specific vulnerabilities. Acute insulin supplementation normalises systemic glucose uptake and rescues stress-induced behavioural deficits. Likewise, empagliflozin-mediated glucose offloading stabilises blood glucose and enhances muscle function to levels comparable with standard care prednisolone. These findings identify endocrine-metabolic decoupling as a central driver of metabolic fragility in DMD, correctable though insulin restoration or targeted glucose redirection.

Extracellular vesicles (EVs) encompass a multitude of lipid bilayer-delimited particles, of which exosomes are the most widely studied. Bidirectional cell–cell communications via EVs have a pivotal role in the physiology of multicellular organisms. EVs carry biological cargoes (including proteins, RNA, DNA, lipids and metabolites) capable of mediating a range of pleiotropic cellular functions. Over the past decade, EVs released by cancer cells (onco-EVs) have been shown to promote cancer progression including tumour outgrowth and metastatic dissemination. Furthermore, the innate ability of EVs to protect vulnerable molecular cargoes (such as RNA, DNA or proteins) from enzymatic degradation, their presence in most biofluids and the ability to transverse biological barriers to reach distant organs make them ideal targeted drug delivery systems, including in patients with cancer. Many of these properties also support investigations of EVs as biomarkers with potential roles in both diagnosis and treatment monitoring. In this Review, we describe advances in the development of EVs as cancer therapeutics or biomarkers, including cancer vaccines, targeted drug delivery systems and immunotherapies, as well as potential roles in early cancer detection, diagnosis and clinical management. We also describe the potential of emerging technologies to support further discoveries as well as the clinical translation of EVs into diagnostic and therapeutic clinical tools. We highlight the potential of single-EV and onco-EV detection and discuss how advances in multi-omic and artificial intelligence-enabled integration are providing new biological insights and driving clinical translation. Extracellular vesicles (EVs), a diverse range of membrane-delimited particles, have multiple cellular functions and, when released by cancer cells, can promote tumour growth and metastatic dissemination. The authors of this Review describe advances in the development of EVs as biomarkers and cancer therapeutics, focusing on clinical translation of EVs into diagnostic and therapeutic clinical tools.

Epithelial-mesenchymal transition (EMT) is a fundamental, dynamic cellular process involved in embryonic development, metastasis, organ fibrosis, and tissue regeneration. To define the molecular landscape of secreted midbody remnants (MBRs) to the EMT process, a proteome analysis of MBRs released from Madin-Darby canine kidney (MDCK) cells and following oncogenic H-Ras transformation (21D1 cells) was performed. MBRs, a new class of membranous extracellular vesicle (EV) molecularly distinct from exosomes/small EVs, were purified using sequential centrifugation/buoyant density gradient centrifugation. Proteomic profiling revealed MDCK cell-MBRs reflect their epithelial origin (e.g., enriched CDH1, DSP, THBS1, OLCN, EPCAM proteins) and 21D1 cell-MBRs their oncogenic and mesenchymal phenotype (e.g., HRAS, VIM, MMP14, CDH2, WNT5A, and enriched invasive and cell motility protein networks). Validation of proteome cargo revealed key protein networks associated with the EMT process in MBRs, and conserved MBR proteome across different cell types. Prominent findings were the unique expression of the immune checkpoint protein NT5E/CD73 (ecto-5 '-nucleotidase) and ser/thr kinases LIMK1/K2 in MBRs from mesenchymal cells following their oncogenic transformation, and enrichment in Wnt signaling network proteins. These data identify the core proteome of MBRs regulated during the dynamic process of EMT and cell transformation over other EV types in context of the EMT process.Summary Epithelial-to-mesenchymal transition (EMT) is a critical cell biological process that occurs during embryonic development and cancer progression. Our study describes sequential purification of secreted midbody remnants (MBRs) and exosomes/sEVs from the in vitro cell line EMT model Madin-Darby canine kidney (MDCK) cells and MDCK cells transformed with oncogenic H-Ras (21D1 cells): Proteomics identified the repertoire of enriched MDCK-MBR proteins following EMT. MBRs display a proteome profile distinct from sEVs that is enriched with factors of the centralspindlin complex (KIF23.1, KIF4A, INCENP, CEP55, PLK1) and further includes components of the mitochondrial network, cytokinesis, microtubule movement, and intercellular connection. In the context of EMT, our data reveal enriched EMT pathways in MBRs including signaling receptor binding, regulation of cell differentiation, and Wnt, VEGF, and PDGF signaling. We have validated these findings in the context of Wnt signaling in other EV types. We identify several mesenchymal-enriched networks in MBRs associated with focal adhesion, cell matrix, kinase activity, and cell shape/organization, while epithelial-derived MBRs show enriched networks predominantly associated with mitochondrial (processing/transport), midbody, and plasma membrane annotation. Our study sheds light on the proteome architecture of MBRs following oncogenic H-Ras-induced EMT in cell transformation: collectively, our data informs ongoing efforts to delineate oncogenic drivers of cancer initiation, progression, and metastasis.

Targeted delivery of therapeutics to lymph nodes (LNs) via minimally invasive subcutaneous injection offers promise to treat B and T cell malignancies, latent HIV-1 reservoirs, and cancer metastasis. However, achieving therapeutic drug levels in subcutaneous tissues and LNs is challenging because of the poor retention and accumulation of soluble drugs. Engineered nanoparticles (NPs) provide a platform for prolonging drug stability and retention in the subcutaneous space and LNs, acting as reservoirs for the sustained release of drugs through the lymphatic system. Yet, their clinical translation for LN drug delivery faces limitations owing to the potential immunogenicity and toxicity of NP material components. Herein, we show that glycogen, a natural and biodegradable polysaccharide NP can be tailored by controlling its size, surface charge, and functional groups to enable the delivery of small and large bioactive molecules in LNs. Upon subcutaneous injection, positively charged glycogen NPs primarily accumulate in the liver and kidneys, whereas negatively charged glycogen NPs accumulate in the liver and lungs, irrespective of their size. Small and positively charged (19 ± 2 nm in diameter; 53 ± 4 mV) glycogen NPs accumulate more efficiently in LNs than the large and positively charged (57 ± 2 nm in diameter; 54 ± 9 mV) or small and negatively charged (13 ± 4 nm in diameter; -27 ± 1 mV) glycogen NPs. Moreover, smaller and slightly positively charged glycogen NPs (16 ± 4 nm in diameter; 10 ± 6 mV) enable the loading and delivery of Cre-recombinase mRNA, small organic molecules and antibodies at the site of injection and LNs. The glycogen NPs are associated with macrophages lining the subcapsular sinus and medullary regions of the LNs but are also detected within the paracortex at the T cell zone. This suggests that the glycogen NPs can overcome the phagocytic cell barrier by saturating the phagocytic capacity of the macrophages at the subcapsular sinus and spread to deeper parts of the paracortex region, providing an avenue for their application in the treatment of lymphatic diseases.

Epithelial-mesenchymal transition (EMT) is a highly conserved morphogenic process that allows highly polarized, immotile epithelial cells to transform into motile mesenchymal cells: it is a fundamental cellular process involved in embryonic development, tumour cell metastasis, organ fibrosis and tissue regeneration. To assess the contribution of secreted midbody remnants (MBRs) - a new class of membranous extracellular vesicle (EV) molecularly distinct from exosomes/small EVs – to the EMT process, we conducted a proteomic analysis of MBRs released from Madin-Darby canine kidney (MDCK) cells, and MDCK cells transformed with oncogenic H-Ras (21D1 cells). MBRs were harvested from cell culture media in milligram quantities using a continuous culture bioreactor device and purified using sequential centrifugation and buoyant density gradient centrifugation (OptiPrep™). Gel-MS/MS protein profiling showed MDCK cell-MBRs reflect their epithelial origin (e.g., enriched CDH1, DSP, THBS1, OLCN, EPCAM proteins) and 21D1 cell-MBRs their mesenchymal phenotype (e.g., HRAS, VIM, MMP14, CDH2, WNT5A and enriched invasive and cell motility proteins). Prominent findings were the unique expression of the immune checkpoint protein NT5E/CD73 (ecto-5′-nucleotidase), and ser/thr kinases LIMK1/K2 in 21D1-MBRs (not present in MDCK cell-MBRs), and enrichment in Wnt signalling network proteins. Collectively, our findings suggest MBRs might play a previously unrecognized role in the EMT process. Significance 1. Epithelial-to-mesenchymal transition (EMT) is a critical cell biological process that occurs during normal embryonic development and cancer progression. Our study describes, for the first time, the large-scale sequential purification of secreted midbody remnants (MBRs) and exosomes/sEVs from the in vitro cell line EMT model Madin-Darby canine kidney (MDCK) cells and MDCK cells transformed with oncogenic H-Ras (21D1 cells): GeLC-MS/MS protein profiling identified the repertoire of enriched MDCK-MBR proteins following EMT. 2. MBRs display a proteome profile distinct from sEVs that is enriched with factors of the centralspindlin complex (KIF23.1, KIF4A, INCENP, CEP55, PLK1) and further include components of the mitochondrial network, cytokinesis, microtubule movement, and intercellular connection. 3. In the context of EMT, our data reveal simultaneous activation of EMT signalling pathways in MBRs including signalling receptor binding, regulation of cell differentiation, and Wnt, VEGF and PDGF signalling. 4. We identify several mesenchymal enriched networks in MBRs associated with focal adhesion, cell matrix, kinase activity, and cell shape/organisation, while epithelial derived MBRs are show enriched networks predominately associated with mitochondrial (processing/transport), midbody, and plasma membrane annotation. 5. Our study sheds light on the signalling architecture of MBRs following oncogenic H- Ras-induced EMT: collectively, our data informs ongoing efforts to delineate oncogenic drivers of cancer initiation, progression, and metastasis. ### Competing Interest Statement The authors have declared no competing interest.

Atrial fibrillation (AF), often accompanied by atrial fibrosis, is challenging to diagnose sub-clinically and reverse once established. Molecular imaging targeting excess atrial collagen may enable earlier detection of atrial fibrosis and its associated arrhythmias. We used the collagen I-binding peptide EP-3533 and our novel ‘T-peptide’ targeting matrix metalloproteinases-2-digested collagen IV to image interstitial atrial fibrosis, AF and heart failure (HF) that develop in the double transgenic mouse model dnPI3K-Mst1 (termed ‘AF + HF’). Ex vivo and in vivo imaging were performed using near-infrared scans and positron emission tomography (PET) with probes conjugated to Cyanine5.5 and copper-64, respectively. Both tracers significantly accumulated in fibrotic atria compared to non-transgenic controls, with specific T-peptide uptake relative to a mutated ‘S-peptide’. Pharmacokinetic profiling demonstrated good tracer plasma stability and fast renal clearance. These results highlight the potential of collagen-targeted peptide tracers, particularly the disease stage-sensitive T-peptide, to improve diagnosis and monitoring of atrial fibrosis and AF.

Triple-negative breast cancer (TNBC) presents a formidable challenge due to its poorest prognosis and limited array of treatment options available. Photodynamic therapy (PDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to insufficient tumor accumulation and therapeutic resistance. Herein, an "all-in-one" tumor-therapeutic nanomedicine named HA@IR780@KU55933@BSA (HIKB) which integrated photosensitizer IR780 with ATM kinase inhibitor KU55933 was designed to facilitate drug delivery and target specific pathways involved in tumor PDT treatment resistance. Co-delivery of IR780 and KU55933 exacerbated intracellular ROS production, mitochondrial dysfunction and DNA damage to form a potent anti-TNBC therapeutic cyclical feedback loop and then induced pyroptosis and apoptosis of TNBC cells by activating the Caspase3/GSDME signaling pathway and regulating apoptosis-related protein expression, respectively. In vivo evaluations in the TNBC orthotopic xenograft mouse model demonstrated that the designed HIKB NPs could accumulate in tumor tissues and exert synergistic therapeutic effects. Altogether, this study described a self-assembling strategy for constructing an all-in-one nanomedicine that effectively integrates multiple therapeutic modalities to provide a comprehensive and systemic approach to tumor suppression.

Metastasis in breast cancer frequently spreads to the bones, significantly impacting patient outcomes and escalating mortality rates. The ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in regulating the DNA damage response (DDR) and has been linked to the invasion and spread of breast cancer. In this study we investigated the regulatory mechanisms of ATM in bone metastasis of breast cancer. The bone metastases models were constructed in female nude mice: The MDA-MB-231 tumor model was generated by implanting luciferase-tagged MDA-MB-231 cells into the left hind tibia and intra-caudal artery. For the SK-BR-3 tumor model, luciferase-tagged SK-BR-3 cells were injected through the intra-caudal artery. By conducting bioinformatics analyses and in vitro and in vivo experiments, we found that ATM expression was markedly elevated in bone metastasis samples compared to liver, lung or skin metastases. We demonstrated that ATM boosted the migrative and invasive abilities and pre-osteoclast differentiation of MDA-MB-231 and SK-BR-3 cell lines via expression of CCL2, an osteoclast-related cytokine. The regulation of ATM on CCL2 was found to be NFκB dependent. In vivo experiments confirmed that ATM knockout (ATM KO) or treatment with small-molecule ATM inhibitor KU55933 markedly inhibited osteoclastogenesis of SK-BR-3 cells and the progression of breast cancer bone metastasis. Our results underscore the pivotal role of ATM in regulating NFκB-CCL2 expression and promoting the progression of breast cancer bone metastasis.

Atherosclerosis (AS) is a major contributor to vascular disorders and represents a significant risk to human health. Currently, first-line pharmacotherapies are associated with substantial side effects, and the development of atherosclerosis is closely linked to dietary factors. This study evaluated the effects of a dietary supplement, EsV3, on AS in apolipoprotein E (ApoE) −/− model mice. The study utilized a high-fat diet-induced ApoE−/− hyperlipidemic mouse model. EsV3 was administered in prophylactic (P-EsV3) and therapeutic regimens for 16 and 12 weeks, respectively, with distinct high- and low-dose groups (0.36 and 1.8 g/kg/day). Serum lipid levels were measured and monitored for body weight and food consumption alterations in murine models. Aortic oil red O staining was conducted to assess plaque formation and calculate the plaque-to-vessel area ratio. Liver tissue changes were examined via HE staining. Moreover, serum oxidative stress markers (MDA, GSH, SOD) were measured to evaluate oxidative damage and lipid metabolism. Both atorvastatin and P-EsV3 treatments significantly lowered TC, TG, and LDL-C levels, with P-EsV3-H enhancing HDL-C levels (P < 0.05). Prophylactic EsV3 administration was more effective than therapeutic administration in regulating TG and LDL-C levels and had comparable effects to atorvastatin on TC and HDL-C. All treatment groups exhibited reduced body weight compared to the model group, with no significant differences in food intake. Additionally, EsV3 administration significantly reduced the aortic plaque area and liver lipid droplets compared to the model group, while mitigating oxidative stress, as evidenced by decreased MDA levels and increased SOD and GSH levels, with outcomes comparable to those observed with atorvastatin. In ApoE−/− hyperlipidemic mice, EsV3 improved lipid profiles and reduced aortic plaque formation. EsV3's effects, attributed partly to its antioxidant properties, were comparable to atorvastatin, suggesting its potential as a preventive and therapeutic agent for hyperlipidemia and atherosclerosis.

Ovarian cancer (OC) is a highly aggressive malignancy with a poor prognosis, necessitating novel therapeutic strategies. Fucoxanthin (FX), a marine-derived carotenoid from Laminaria japonica, has demonstrated promising anticancer potential. This study revealed that FX exerts multiple anticancer effects in OC by inhibiting cell proliferation, invasion, and migration, while inducing various forms of programmed cell death (PCD). FX triggered PANoptosis (apoptosis, necroptosis, and pyroptosis) and ferroptosis. FX treatment regulated key markers associated with PANoptosis, including apoptosis (Bcl-2, cleaved caspase-3), pyroptosis (GSDME), and necroptosis (RIPK3). Additionally, FX treatment modulated ferroptosis-related markers, such as SLC7A11 and GPX4, while increasing reactive oxygen species (ROS) and Fe2+ levels and disrupting mitochondrial function. Proteomic and molecular docking analyses identified AMP-activated protein kinase (AMPK) as a direct FX target, activating the AMPK/Nrf2/HMOX1 pathway to promote ferroptosis. In vivo, FX significantly reduced tumor growth in OC xenograft models, accompanied by enhanced ferroptosis marker expression. These findings demonstrate that FX induces ferroptosis through the AMPK/Nrf2/HMOX1 pathway and promotes PANoptosis via distinct mechanisms, highlighting its potential as a marine-derived therapeutic agent for OC.

Thrombolytic agents are serine proteases or related enzymes that facilitate blood clot breakdown via a process called thrombolysis. They work either indirectly, via activation of plasminogen into plasmin—a potent fibrin-degrading enzyme—or by direct dissolution of fibrin within clots. Numerous clinical trials investigating thrombolytic candidates for major thrombotic conditions, such as heart attack and acute ischaemic stroke (AIS), have led to the development of several potential therapies. However, while some drugs show clinical benefits, most still possess substantial limitations, especially for the treatment of AIS. Recombinant tissue-type plasminogen activator (rt-PA; alteplase) was the only clot-busting medication officially approved by the Food and Drug Administration for AIS from 1996 until 2024, until the recent approval of its mutated version, tenecteplase (2025). However, the use of rt-PA is significantly limited by its short plasma half-life, and both rt-PA and tenecteplase possess reduced efficacy against platelet-rich thrombi and a narrow, guideline-recommended therapeutic window up to 4.5 hours from stroke onset, primarily due to a diminished risk-benefit profile beyond this time point. While recent thrombectomy techniques offer ground-breaking ways for the removal of large clots, a pressing need remains to improve pharmacological thrombolysis. Novel strategies, including the fusion of clot-busting enzymes with thrombus-targeting antibodies and nanotechnology-based delivery systems, are being tested for their ability to increase the precision and safety of thrombolytic therapy. This review will articulate the historical milestones in thrombolysis, discuss key thrombolytic agents and their generational derivatives, and explore innovative approaches to advance this life-saving therapy for AIS.

The treatment and management of kidney diseases present a significant global challenge, affecting over 800 million individuals and necessitating innovative therapeutic strategies that transcend symptomatic relief. The application of nanotechnology to therapies for kidney diseases, while still in its early stages, holds transformative potential for improving treatment outcomes. Recent advancements in nanoparticle-based drug delivery leverage the unique physicochemical properties of nanoparticles for targeted and controlled therapeutic delivery to the kidneys. Current research is focused on understanding the functional and phenotypic changes in kidney cells during both acute and chronic conditions, allowing for the identification of optimal target cells. In addition, the development of tailored nanomedicines enhances their retention and binding to key renal membranes and cell populations, ultimately improving localization, tolerability, and efficacy. However, significant barriers remain, including inconsistent nanoparticle synthesis and the complexity of kidney-specific targeting. To overcome these challenges, the field requires advanced synthesis techniques, refined targeting strategies, and the establishment of animal models that accurately reflect human kidney diseases. These efforts are critical for the clinical application of nanotherapeutics, which promise novel solutions for kidney disease management. This review evaluates a substantial body of in vivo research, highlighting the prospects, challenges, and opportunities presented by nanotechnology-mediated therapies and their potential to transform kidney disease treatment.

Insulin replacement therapy is essential for the management of diabetes. However, despite the relative success of this therapeutic strategy, there is still a need to improve glycaemic control and the overall quality of life of patients. This need has driven research into orally available, glucose‐responsive and rapid‐acting insulins. A key consideration during analogue development is formulation stability, which can be improved via the replacement of insulin's A6–A11 disulfide bond with stable mimetics. Unfortunately, analogues such as these require extensive chemical synthesis to incorporate the nonnative cross‐links, which is not a scalable synthetic approach. To address this issue, we demonstrate proof of principle for the semisynthesis of insulin analogues bearing nonnative A6–A11 cystine isosteres. The key feature of our synthetic strategy involves the use of several biosynthetically derived peptide precursors which can be produced at scale cost‐effectively and a small, chemically synthesised A6–A11 macrocyclic lactam fragment. Although the assembled A6–A11 lactam insulin possesses poor biological activity in vitro, our synthetic strategy can be applied to other disulfide mimetics that have been shown to improve thermal stability without significantly affecting activity and structure. Moreover, we envisage that this new semisynthetic approach will underpin a new generation of hyperstable proteomimetics.

IntroductionTriple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance.ObjectivesFucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop.Methods and resultsHerein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis.ConclusionSystematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.

Effective EPR and tumor penetration are bottlenecks in current nanomedicine therapy. Comosol software was utilized to analyze the motion process of nanoparticles (NPs) with different shapes, from blood vessels to tumor tissue, to address this. By calculation, urchin-like NPs experienced higher drag forces than spherical NPs, facilitating their EPR and tumor penetration effects. Thus, urchin-like indocyanine green-loaded hydroxyethyl starch-cholesterol (ICG@HES-CH) NPs were prepared by leveraging the instability of ICG responding to near-infrared light (NIR). Upon NIR exposure, ICG degraded and partly disintegrated ICG@HES-CH NPs, and its morphology transformed from spherical to urchin-like. Vincristine (VC), as a model drug, was loaded in urchin-like ICG@HES-CH NPs for the treatment of lymphoma. A20 lymphoma cells and 3T3-A20 tumor organoids were employed to investigate the influence of shape on NPs' cellular uptake, penetration pathway, and cytotoxicity. It demonstrated that urchin-like ICG@HES-CH NPs mainly transport across the extracellular matrix through intercellular pathways, easily reaching the deep tumor sites and achieving higher cytotoxicity. In vivo VC distribution and anti-tumor results indicated that urchin-like NPs increased VC EPR and penetration ability, lowering VC neurotoxicity and superior anti-tumor effect. Therefore, urchin-like ICG@HES-CH NPs have great translational potential to be used as chemotherapeutic nanocarriers in anticancer therapy.

Previously, we reported that human primary (SW480) and metastatic (SW620) colorectal (CRC) cells release three classes of membrane-encapsulated extracellular vesicles (EVs); midbody remnants (MBRs), exosomes (Exos), and microparticles (MPs). We reported that MBRs were molecularly distinct at the protein level. To gain further biochemical insights into MBRs, Exos, and MPs and their emerging role in CRC, we performed, and report here, for the first time, a comprehensive transcriptome and long noncoding RNA sequencing analysis and fusion gene identification of these three EV classes using the next-generation RNA sequencing technique. Differential transcript expression analysis revealed that MBRs have a distinct transcriptomic profile compared to Exos and MPs with a high enrichment of mitochondrial transcripts lncRNA/pseudogene transcripts that are predicted to bind to ribonucleoprotein complexes, spliceosome, and RNA/stress granule proteins. A salient finding from this study is a high enrichment of several fusion genes in MBRs compared to Exos, MPs, and cell lysates from their parental cells such as MSH2 (gene encoded DNA mismatch repair protein MSH2). This suggests potential EV-liquid biopsy targets for cancer detection. Importantly, the expression of cancer progression-related transcripts found in EV classes derived from SW480 (EGFR) and SW620 (MET and MACCA1) cell lines reflects their parental cell types. Our study is the report of RNA and fusion gene compositions within MBRs (including Exos and MPs) that could have an impact on EV functionality in cancer progression and detection using EV-based RNA/ fusion gene candidates for cancer biomarkers.

The treatment and management of kidney diseases present a significant global challenge, affecting over 800 million individuals and necessitating innovative therapeutic strategies that transcend symptomatic relief. The application of nanotechnology to therapies for kidney diseases, while still in its early stages, holds transformative potential for improving treatment outcomes. Recent advancements in nanoparticle-based drug delivery leverage the unique physicochemical properties of nanoparticles for targeted and controlled therapeutic delivery to the kidneys. Current research is focused on understanding the functional and phenotypic changes in kidney cells during both acute and chronic conditions, allowing for the identification of optimal target cells. In addition, the development of tailored nanomedicines enhances their retention and binding to key renal membranes and cell populations, ultimately improving localization, tolerability, and efficacy. However, significant barriers remain, including inconsistent nanoparticle synthesis and the complexity of kidney-specific targeting. To overcome these challenges, the field requires advanced synthesis techniques, refined targeting strategies, and the establishment of animal models that accurately reflect human kidney diseases. These efforts are critical for the clinical application of nanotherapeutics, which promise novel solutions for kidney disease management. This review evaluates a substantial body of in vivo research, highlighting the prospects, challenges, and opportunities presented by nanotechnology-mediated therapies and their potential to transform kidney disease treatment.

Acute myeloid leukemia (AML) is a malignant blood disorder and the most common type of acute leukemia in adults. Notwithstanding the plethora of therapeutic modalities, a significant cohort of patients fail to respond to treatment and experience relapse. Anoikis, a distinct modality of programmed cell death, has been linked to cancer progression. However, the prognostic significance of anoikis in AML remains unclear. In this study, a non-negative matrix factorization algorithm was utilized to efficiently reduce the dimensions of merged datasets. We used differential analysis, weighted gene co-expression network analysis (WGCNA), univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression to identify genes associated with prognosis and develop a risk scoring model. Immunohistochemistry was conducted to assess the expression levels of key genes in clinical samples. The association between risk score and the tumor microenvironment (TME), stemness, clinical characteristics, and immunotherapy was evaluated. We identified 41 AML anoikis-related genes (ANRGs) related to survival, and seven genes were chosen to develop prognostic models. The prognostic risk score combined with the clinical and pathological features of AML was used to develop a nomogram, and decision curve analysis demonstrated the net clinical benefit of the model. Furthermore, analysis of ANRGs revealed that PDGFRB inhibition significantly reduced the proliferation of AML cells, promoted apoptosis, and inhibited AML progression both in vitro and in vivo, indicating that PDGFRB plays a crucial role in AML development.