ID: 37742067
Title: Photoacoustic Imaging Endometriosis Lesions with Nanoparticulate Polydopamine as a Contrast Agent.
Abstract: Endometriosis (EM) is a prevalent and debilitating gynecological disorder primarily affecting women of reproductive age. The diagnosis of EM is historically hampered by delays, owing to the absence of reliable diagnostic and monitoring techniques. Herein, it is reported that photoacoustic imaging can be a noninvasive modality for deep-seated EM by employing a hyaluronic-acid-modified polydopamine (PDA@HA) nanoparticle as the contrast agent. The PDA@HA nanoparticles exhibit inherent absorption and photothermal effects when exposed to near-infrared light, proficiently converting thermal energy into sound waves. Leveraging the targeting properties of HA, distinct photoacoustic signals emanating from the periphery of orthotopic EM lesions are observed. These findings are corroborated through anatomical observations and in vivo experiments involving mice with green fluorescent protein-labeled EM lesions. Moreover, the changes in photoacoustic intensity over a 24 h period reflect the dynamic evolution of PDA@HA nanoparticle biodistribution. Through the utilization of a photoacoustic ultrasound modality, in vivo assessments of EM lesion volumes are conducted. This innovative approach not only facilitates real-time monitoring of the therapeutic kinetics of candidate drugs but also obviates the need for the sacrifice of experimental mice. As such, this study presents a promising avenue for enhancing the diagnosis and drug-screening processes of EM.

ID: 38570846
Title: Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.
Abstract: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-β1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

ID: 39270628
Title: Engineering extracellular vesicles derived from endothelial cells sheared by laminar flow for anti-atherosclerotic therapy through reprogramming macrophage.
Abstract: Extracellular vesicles (EVs) secreted by endothelial cells in response to blood laminar flow play a crucial role in maintaining vascular homeostasis. However, the potential of these EVs to modulate the immune microenvironment within plaques for treating atherosclerosis remains unclear. Here, we present compelling evidence that EVs secreted by endothelial cells sheared by atheroprotective laminar shear stress (LSS-EVs) exhibit excellent immunoregulatory effects against atherosclerosis. LSS-EVs demonstrated a robust capacity to induce the conversion of M1-type macrophages into M2-type macrophages. Mechanistic investigations confirmed that LSS-EVs were enriched in miR-34c-5p and reprogrammed macrophages by targeting the TGF-β-Smad3 signaling pathway. Moreover, we employed click chemistry to modify hyaluronic acid (HA) on the surface of LSS-EVs, enabling specific binding to the CD44 receptor expressed by inflammatory macrophages within plaques. These HA-modified LSS-EVs (HA@LSS-EVs) exhibited exceptional abilities for targeting atherosclerosis and demonstrated promising therapeutic effects both in vitro and in vivo.

ID: 39551341
Title: Hyaluronic acid-modified extracellular vesicles for targeted doxorubicin delivery in hepatocellular carcinoma.
Abstract: Hepatocellular carcinoma (HCC), a prevalent and deadly cancer, poses a significant challenge with current treatments due to limitations such as poor stability, off-target effects, and severe side effects. Extracellular vesicles (EVs), derived from tumor cells, have the remarkable ability to home back to their cells of origin and can serve as Trojan horses for drug delivery. CD44, a cell surface glycoprotein, promotes cancer stem cell-like properties and is linked to poor prognosis and resistance to chemotherapy in HCC. Therefore, targeting CD44-expressing HCC cells is of interest in the development of novel therapeutic strategies for the treatment of HCC. In this study, we developed tumor cell-derived EVs (TEVs) functionalized with hyaluronic acid (HA) to serve as natural carriers for the precise delivery of doxorubicin (Dox), which specifically targets HCC cells expressing CD44. Our results demonstrated that HA-engineered EVs (HA-EVs) significantly enhanced Dox accumulation within HCC cells. In a mouse model, HA-EVs effectively delivered Dox to tumors, suppressing their growth and progression while minimizing systemic toxicity. This study demonstrates the potential of HA-functionalized EVs as a novel and targeted therapeutic platform for HCC, offering a valuable strategy for improving drug delivery and patient outcomes. This study presents a promising strategy to advance targeted chemotherapy for HCC and address the challenges associated with conventional treatments. Engineered HA-functionalized EVs offer a tailored and efficient approach to increase drug delivery precision, underscoring their potential as a novel therapeutic platform in the realm of HCC treatment.

ID: 39923538
Title: Glycoengineered stem cell-derived extracellular vesicles for targeted therapy of acute kidney injury.
Abstract: Acute kidney injury (AKI) is associated with high morbidity and mortality rates, primarily due to the lack of effective therapeutic options for kidney repair. To restore the biological function of injured kidney, there is a need to protect renal tubular epithelial cells (RTECs) and regulate M1 macrophages, responsible for progress of AKI. Herein, based on metabolic glycoengineering-mediated click chemistry, we prepare the engineered extracellular vesicles (pSEVs), derived from PEGylated hyaluronic acid (HA)-modified mesenchymal stem cells. Owing to their cell-protective and anti-inflammatory properties, pSEVs effectively prevent the apoptosis of RTECs and inhibit the polarization of macrophages into an inflammatory phenotype in vitro. When systemically administered into the cisplatin-induced AKI animal model, pSEVs selectively accumulate in injured kidneys via HA-mediated binding to CD44 and toll-like receptor4 which are over-expressed on RTECs and M1 macrophages, respectively. This targeted delivery efficiently alleviates AKI-related symptoms, as evidenced by delayed kidney weight reduction, and decreased levels of creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. Overall, pSEVs show potent anti-inflammatory effects and specific targeting to injured kidneys, presenting a considerable potential as the therapeutics for AKI.

ID: 39957840
Title: Engineering and Monitoring the Sustained Release of Extracellular Vesicles from Hydrogels for In Vivo Therapeutic Applications.
Abstract: Extracellular vesicles (EVs) are gaining interest in regenerative medicine and biomaterials have been shown to extend EV bioavailability following delivery. Here, we report the labeling of both hydrogels and EVs to better understand hydrogel design for sustained EV release into tissues. Shear-thinning hydrogels were engineered using guest-host (i.e., adamantane-cyclodextrin) modifications to hyaluronic acid (GH), as well as GH hydrogels with the addition of gelatin crosslinked via transglutaminase (GH+Gel) to temporally control hydrogel properties. When labeled with a near-IR dye and injected into rat myocardial tissue, the GH+Gel hydrogel was retained (>14 days) longer than the GH hydrogel alone (~7 days), likely due to the added gelatin network. To overcome challenges associated with common EV labeling methods, we utilized a highly versatile metabolic labeling methodology via the incorporation of Ac4ManNAz during EV synthesis to introduce azide groups that could then be reacted with DBCO-dyes. When injected in saline, EVs were cleared within 24 hours in hearts; however, hydrogels enhanced EV retention, with levels based on hydrogel degradation behavior, namely >14 days for GH+Gel hydrogel and ~7 days for GH hydrogel alone. These findings support the use of hydrogels in EV therapies to help retain their presence at desired tissue sites.

ID: 40468893
Title: Hyaluronic acid-engineered milk extracellular vesicles to target triple negative breast cancer through CD44.
Abstract: Cancer therapy remains a challenge in healthcare, particularly in the context of triple-negative breast cancer (TNBC), where targeted therapies are still scarce. Addressing this issue, our study explores a novel targeting approach using small extracellular vesicles (sEVs) isolated from cow milk, functionalized with hyaluronic acid (HA) to target the overexpressed cluster of differentiation 44 (CD44) cell surface receptor in TNBC cells. A method for isolating sEVs from cow milk was optimized, and the obtained sEVs were fully characterized in terms of size, morphology, and protein markers. Subsequently, milk-derived sEVs were covalently bound with HA of varying molecular weights (MW, 20-60 kDa, 250 kDa, 1000-1600 kDa) and binding and internalization dynamics were investigated. Breast cancer cell lines, MDA-MB-231 (TNBC and CD44+) and MCF-7 (CD44-), were used as in vitro models to evaluate CD44 selectivity. The binding and internalization studies unveiled enhanced selectivity of functionalized sEVs for CD44-overexpressing cells compared to non-functionalized sEVs. Notably, higher MW HA exhibited enhanced binding capacity, with partial internalization occurring through CD44 endocytic mechanisms. In summary, this work introduces a sEVs isolation method and sheds light on the role of HA MW in enhancing cellular uptake of CD44 overexpressing cancer cells.

ID: 40592115
Title: Multifunctional silver nanoclusters with hyaluronic acid for dual-targeted tumor imaging and ROS-mediated therapy.
Abstract: Despite their potential in cancer theranostics, silver nanoparticles (Ag NPs) face significant clinical translation challenges, including polydispersity, weak fluorescence emission, and suboptimal biocompatibility. To overcome these challenges, we introduce Ag@PEG2000-HA nanoclusters (NCs), novel silver-based NCs developed through a sequential functionalization process using polyethylene glycol (PEG) and hyaluronic acid (HA). The HA-induced stabilization enlarges nanocluster cores and promotes ligand-metal charge transfer, synergizing with size-dependent aggregation-induced emission (AIE) effect to amplify fluorescence. These developed nanoconstructs showcase enhanced theranostic capabilities, featuring strong near-infrared (NIR) fluorescence for live tumor imaging and reactive oxygen species (ROS)-enabled mitochondrial targeting to induce cancer cell apoptosis selectively. Systematic evaluations, both in vitro and in vivo, confirmed significant tumor growth inhibition, increased survival rates, and a positive biosafety profile. The dual-targeting approach, leveraging the enhanced permeability and retention (EPR) effect alongside HA-mediated CD44 interaction, ensures precise tumor targeting and reduces off-target effects. Additionally, the nanoclusters showed exceptional stability, extended blood circulation, and resistance to macrophage phagocytosis, thereby enhancing their therapeutic effectiveness. Detailed mechanistic studies showed that Ag@PEG2000-HA NCs trigger apoptosis via ROS production and mitochondrial disruption, and concurrently reduce the expression of key tumor-associated proteins (CD31, Ki-67, and MMP9), inhibiting angiogenesis, proliferation, and metastasis. This research establishes a multifunctional nanoplatform bridging diagnostic imaging and therapy, opening new avenues for precision oncology. The findings provide fundamental insights into the design principles of cluster-based theranostic nanomaterials, paving the way for their clinical translation in cancer treatment.

ID: 40813270
Title: AntiCD44 antibody-conjugated gold nanoparticles for targeted photothermal therapy of endometriotic cells.
Abstract: Endometriosis is a chronic gynecologic disease that needs newer and safer treatments. The proposed work aims to develop a nanosystem based on gold nanoparticles (AuNPs) to actively target human endometriosis CD44(+) cells and significantly reduce their viability by photothermal therapy (PTT). AuNPs stabilized by lipoic acid-Poly(ethylene glycol)-Maleimide (LA-PEG-Mal) (Au@P) were decorated with antiCD44 antibodies (Au@P_AbCD44) through maleimide chemistry. The physicochemical and biochemical approaches revealed the presence of the antibody on Au@P_AbCD44. The in vitro studies were conducted against overexpressing CD44 cells (12Z), low-expressing CD44 cells (HESC), and the normal fibroblast cell line (NIH-3T3). Following the internalization through the clathrin-mediated endocytosis, the PTT of the cell-internalized Au@P_AbCD44 was investigated using two distinct laser types, due to the differing Au@P's LSPR properties. Au@P_AbCD44 exhibited significant PTT efficacy against 12Z cells; however, GNS@P_AbCD44 required lower energy input compared to GNP@P_AbCD44. This enhanced performance is attributed to the LSPR-mediated photothermal conversion efficiency of GNS over GNPs.In both cases, the apoptotic pathway was selected by dying cells over necrotic cells. The results revealed a better photothermal ability of GNS@P_AbCD44 compared to GNP@P_AbCD44. Our findings highlight the clinical potential of gold nanostars as advanced photosensitizers for targeted photothermal therapy, offering a promising strategy for more effective and less invasive treatment of endometriosis.

ID: 40838562
Title: Harnessing Biomaterials for Gene Therapy in Autoimmune Disease.
Abstract: The integration of biomaterials and gene therapy heralds a transformative approach for treating autoimmune diseases, which are characterized by immune dysregulation and chronic inflammation. Conventional therapies often suffer from systemic toxicity and nonspecific immunosuppression, highlighting the need for precision medicine strategies. This review highlights recent breakthroughs in biomaterial-assisted delivery of gene therapy tools, such as small interfering RNA (siRNA), messenger RNA (mRNA), and clustered regularly interspaced short palindromic repeats-CRISPR-associated 9 (CRISPR-Cas9). Advanced biomaterials, including lipid nanoparticles, polymeric micelles, inorganic nanoparticles (such as gold [Au] and graphene oxide [GO]), and extracellular vesicles (EVs), have been engineered to overcome key challenges, such as low targeting efficiency, enzymatic degradation, and off-target effects. Functionalized systems that leverage pH-, reactive oxygen species (ROS)-, or enzyme-responsive mechanisms enable spatiotemporally controlled release, thereby reducing off-target exposure and systemic toxicity, for example, by confining TNF-α siRNA release to inflamed joints in rheumatoid arthritis (RA). In contrast, ligand/receptor-mediated targeting (such as folate and CD44) enhances tissue specificity. This review highlights the pivotal role of biomaterials in improving the clinical translation of gene therapy, providing a roadmap for next-generation treatments that prioritize precision, durability, and minimal systemic effects.

ID: 41071973
Title: Extracellular Vesicles as Novel Biomarkers for Tumor Association in Intermediate-Risk Paraneoplastic Neurologic Syndromes.
Abstract: Paraneoplastic neurologic syndromes (PNS) are cancer-related neurologic disorders caused by an autoimmune response targeting both the tumor and the nervous system. Identifying new biomarkers for early cancer detection could improve treatment outcomes. Tumor-derived cells release extracellular vesicles (EVs) carrying tumor-specific molecular signatures, which can help distinguish patients with cancer even in early stages. The aim of this study was to assess the potential of EVs as biomarkers to enhance cancer detection in patients with PNS. This observational and multicenter study included 27 patients with tumor-associated PNS, 26 with suspected PNS without a tumor, 35 with cancer, and 32 healthy controls. Subsequently, among the patients with PNS, individuals were subclassified according to the PNS-Care Score as definite, probable, possible, and non-PNS. Total EVs were isolated from blood by precipitation and from B cells, T cells, and neurons by immunoisolation. To identify a biomarker for diagnostic refinement and clinical stratification, EV levels, size, and protein content were compared across study groups. To find a tumor biomarker in intermediate-risk cases, the possible association between EV protein content and cancer detection in intermediate-risk syndromes was analyzed. Patients with tumor-associated PNS showed significantly higher circulating EV levels compared with those with suspected PNS without evidence of a tumor (p = 0.028). Moreover, total EV levels, along with B cell-derived EVs, effectively differentiated patients with definite PNS from those with probable (p = 0.05) and possible (p = 0.006) PNS. A cutoff value of 2.10 × 1010 particles/mL EVs was identified, above which diagnosis of PNS was definite, with 86% sensitivity and 81% specificity. Proteomic analysis identified specific proteins, including ACADM, HPT, ACTBL, and CCAR2, as markers of definite PNS, differentiating such patients from those with probable and possible PNS, contributing to diagnostic refinement for clinical stratification. It is important to note that increased levels of EVs and CD44 distinguished intermediate-risk cases with tumors from those without. EVs may act as tumor biomarkers in patients with PNS, even in intermediate-risk cases. This study provides Class IV evidence that higher circulating blood levels of EVs can distinguish between tumor-associated PNS from suspected PNS without tumor.

ID: 41429389
Title: Quercetin-loaded zeolitic imidazolate framework-8 nanoparticles through borneol-embedded hyaluronic acid hydrogel for ischemic stroke treatment.
Abstract: Ischemic stroke (IS), widely known for the frequency and the high disability rate, remains challenging to conquer due to its complex pathology. The therapeutic application of Quercetin (QC), a natural flavonoid with powerful antioxidant and anti-inflammatory activities, its therapeutic application is limited by low bioavailability，and so is the blood-brain barrier (BBB)，with a major obstacle in the effective delivery of drugs to the brain. In view of the above, this study aimed to develop an intranasal administration (IN) system based on borneol (Bo) embedded thermosensitive hydrogel, to deliver QC-loaded zeolite imidazolate framework-8 (ZIF-8) nanoparticles (QC@ZIF-8 NPs) for the synergistic treatment of IS. Up to now, QC@ZIF-8 NPs with uniform particle size and pH-responsive release characteristics has been successfully synthesized. And with its ideal property of temperature-sensitivity, bio-compatibility and release-sustainability, the prepared Bo/QC@ZIF-8-Gel was evaluated through in vitro experiments (MTT, LDH, ROS, JC-1, immunofluorescence, ELISA) to test its neuro-protective, anti-inflammatory, and antioxidant properties. The results showed that Bo/QC@ZIF-8-Gel effectively scavenged ROS, attenuated OGD/R-induced cell damage, and significantly lowered the levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6) by promoting microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Besides, pharmacokinetic studies in rats showed that borneol significantly promoted drug enrichment in the brain following the IN of this gel system. Furthermore, in a rat model of the middle cerebral artery occlusion (MCAO), we evaluated the brain targeting of Bo/QC@ZIF-8-Gel (via in vivo imaging), as well as its effects on the cerebral infarct volume and the neurological function. The results showed that Bo/QC@ZIF-8-Gel treatment significantly reduced the cerebral infarct volume, improved the neurological function scores, increased the number of surviving neurons, effectively inhibited the inflammatory response in the brain, and promoted the neurological recovery in MCAO model rats. In summary, Bo/QC@ZIF-8-Gel represents a promising strategy for the treatment of IS.

ID: 41570918
Title: Targeting endometrial stem cell in endometriosis treatment, a scoping review.
Abstract: Endometriosis is characterized by the ectopic implantation of endometrial tissue affecting reproductive-aged women. Available therapies have still unmet needs namely due to recurrence rates and systemic side effects. Emerging evidence suggests endometrial stem cells (EnSCs) contribution in disease pathogenesis, including mesenchymal stem cells (E-MSCs), epithelial progenitor cells (EPCs), and side population cells (ESPs). These stem/progenitor cells are involved in proliferation, migration, and angiogenesis, contributing to endometriosis genesis and persistence. Targeting EnSCs and their regulatory pathways present a promising therapeutic strategy to improve unmet needs in endometriosis. This scoping review was based on a systematic literature search conducted in PubMed, EMBASE, and Web of Science considering studies published after 2000. Inclusion criteria focused on original research articles exploring the role and targeting of EnSCs in endometriosis, following PRISMA-ScR guidelines. Data were synthesized through narrative and descriptive methods. The review structures key pathways and therapeutic agents targeting EnSCs in endometriosis. Notch1, PI3K/Akt, Wnt/β-catenin, and JAK/STAT signalling are pathways that regulate proliferation, migration and survival of EnSCs in endometriosis. Agents such as metformin, lovastatin, sorafenib, quinagolide, and γ-secretase inhibitors demonstrated potential to modulate stemness, leading to a decrease in inflammation, migration and apoptosis. Anti-angiogenic agents showed efficacy in reducing lesion size In vivo, targeting E-MSCs. Exosomes emerge as a cell-free approach, derived from menstrual stem cells (MenSCs) or ginger-based nanoparticles and exhibited properties essential for endometriosis treatment, directed to ectopic stem cells. EnSCs sustain aberrant cellular behaviours in endometriosis. Targeting EnSCs and their related pathways may be an innovative, individualized, and disease-modifying strategy. Pharmacological modulation, gene therapy and exosome are strategies for stem cell inhibition in endometriosis, being a promising avenue for future research leading to application in clinical practice.

ID: 41582184
Title: Identification of candidate microRNA biomarkers of endometriosis in different bodily fluids.
Abstract: Endometriosis is a chronic estrogen-dependent disorder affecting up to 10% of women of reproductive age, and the absence of reliable noninvasive diagnostic tools contributes to delayed diagnosis and disease progression. To identify potential biomarkers, we profiled miRNA expression in serum, saliva, and vaginal mucus from 20 women (10 with endometriosis and 10 controls) using next-generation sequencing. Differentially expressed miRNAs were identified, and their predicted targets underwent Gene Ontology and KEGG pathway enrichment analyses. Serum proteomics by data-independent acquisition LC–MS/MS was integrated with miRNA data to construct potential miRNA–protein interaction networks. Distinct miRNA profiles were observed across the three bodily fluids, with serum showing the most abundant miRNAs and saliva the lowest. Thirteen, three, and six differentially expressed miRNAs were detected in serum, saliva, and vaginal mucus, respectively. Enrichment analysis implicated apoptosis, Wnt signaling, autophagy, and cellular senescence. Integrated analysis revealed 59 upregulated serum proteins targeted by dysregulated miRNAs, including WNK2, CD44, USP15, GNAI3, HUWE1, and NRAS. ROC analysis suggested that serum miR-200a-3p and miR-200b-3p, may have potential utility as noninvasive biomarkers for the diagnosis and monitoring of endometriosis, pending further validation.

ID: 41711665
Title: Human Endometriotic Lesion-Derived Small Extracellular Vesicles Impair Macrophage Function in the Peritoneal Microenvironment.
Abstract: Endometriosis (EM) is a chronic inflammatory disease that affects ∼10% of women during reproductive age. It is characterised by ectopic (ECT) growth of endometrial-like tissue mainly in the pelvic cavity. Small extracellular vesicles (sEVs) mediate cellular interactions, but their function remains poorly understood in the pathogenesis of EM. 3D endometrial epithelial organoids (EEOs) from ECT lesions and eutopic (EUT) endometrium from EM patients and controls were established to investigate sEVs. Multiplex bead-based flow cytometry revealed CD133/1 and EpCAM as dominant markers on EEO-sEVs, with ECT EEO-sEVs showing upregulation of CD44, CD29 and downregulation of EpCAM compared to EUT EEO-sEVs. Peritoneal fluid (PF)-sEVs displayed high and correlated CD133/1 and EpCAM expression, indicating a major contribution from endometrial epithelial (EE) cells, alongside sEVs of lymphocyte and endothelial origin. Functionally, both ECT EEO-sEVs and PF-sEVs from EM patients significantly suppressed macrophage phagocytosis, as assessed by pH-sensitive fluorescent bioparticles. The effect was reversed by CD47 blockade. The coexpression of CD47 with CD133/1 and EpCAM on PF-sEVs indicates the involvement of EE cell-derived sEVs in CD47/SIRP-α mediated suppression. This study provides the first thorough characterisation of EE-derived sEVs utilising EEO models in EM and demonstrates their potential immunomodulatory role in the peritoneal microenvironment via CD47/SIRP-α signalling.

ID: 41723471
Title: Improving wound healing function and storage stability of stem cell-derived extracellular vesicles via lyophilized hyaluronic acid formulation.
Abstract: Although therapeutic extracellular vesicles (EVs) hold great promise for clinical applications, their limited targeting efficiency and poor storage stability remain critical barriers to clinical translation. Here, we present a lyophilized hyaluronic acid (HA)-coated formulation of EVs derived from human adipose stem cells, engineered to enhance both therapeutic efficacy and long-term preservation. This formulation leverages the natural affinity between HA and the CD44 proteins expressed on the EV membranes, forming stable HA-EV complexes that remain intact following lyophilization and rehydration. These HA-EVs exhibited superior targeting of CD44-expressing cells, including pro-inflammatory macrophages and senescent dermal fibroblasts, thereby effectively suppressing inflammatory responses and restoring fibroblast function in a wound-healing mouse model. Notably, HA-EVs significantly accelerate wound healing by promoting collagen synthesis within the dermal layer, outperforming bare EVs. Furthermore, HA served as an effective cryoprotectant, preserving the physicochemical and biological integrity of EVs for at least six months at 4 ℃. Taken together, our results establish lyophilized HA-EVs as a robust and clinically translatable platform that integrates cell-specific targeting with long-term storage stability for regenerative medicine applications.

ID: 41885409
Title: Hyaluronic Acid Decoration Facilitates CD44-Mediated Targeting and Alters Protein Corona Formation of Extracellular Vesicles.
Abstract: Cell recognition and uptake of extracellular vesicles (EVs) is mediated by a variety of surface molecules. Growing interest has recently been drawn towards glycan structures on EVs. Hyaluronic acid (HA) is a negatively charged glycosaminoglycan that can decorate the surface of EVs from different origins. HA is a ligand for adhesion receptor CD44, which is overexpressed in various cancers and inflammatory diseases. Although HA has been utilised as a surface decoration to improve CD44-mediated targeting of synthetic nanoparticles and EVs, the role of CD44 in the uptake of EVs is not well known. To assess the importance of CD44 in the interactions and endocytosis of HA-decorated EVs, uptake of HA-decorated and nondecorated EVs into CD44-expressing and -deficient cells was investigated using microscopic methods. The uptake of HA-decorated EVs was significantly increased into cells that expressed CD44, but no differences in endocytosis mechanisms were found. Additionally, the formation of plasma-derived protein corona in HA-decorated and nondecorated EVs was investigated using multi-parametric surface plasmon resonance and mass spectrometry. HA-decoration was found to cause a formation of thicker corona and enrichment of plasma-derived protein corona components. These findings highlight the role of HA in enhancing CD44-mediated EV targeting and modulating the composition of protein corona.

ID: 41948730
Title: Hyaluronic acid: emerging roles and biomaterial innovations in Alzheimer's and Parkinson's disease therapy.
Abstract: Hyaluronic acid (HA) is a key component of the extracellular matrix (ECM). Owing to its anti-inflammatory properties, biocompatibility and ability to contribute to ECM remodeling, HA is considered a promising therapeutic candidate for neurodegenerative diseases. This review summarizes the application of HA to treat Alzheimer's disease (AD) and Parkinson's disease (PD) and outlines the current understanding of the mechanism of action and strategies for HA-based biomaterial modification. For AD, HA is involved in several mechanisms including stabilizing the perineuronal net, reducing the toxic effects of Aβ and hyperphosphorylated tau, and modulating neuroinflammation through CD44/RHAMM signaling pathways. HA-based nanoparticles and hydrogels enhance drug delivery across the blood-brain barrier, facilitate Aβ clearance, and enable sustained, controlled release of therapeutic agents. In PD, HA regulates autophagic flux, inhibits α-synuclein propagation, and remodels the ECM to protect dopaminergic neurons. Modifications such as HA hydrogels with neurotrophic factors improve cell transplantation outcomes, while conjugates enhance mitochondrial targeting and dopamine delivery. While numerous preclinical studies have shown promise, significant challenges remain, including the high variability of HA formulations, limited blood-brain barrier penetration efficiency, and a paucity of well-designed clinical trials to validate preliminary findings. Future directions include standardizing laboratory protocols, developing hybrid systems integrating vascular endothelial growth factor and gene therapy, and adopting a patient-specific approach that leverages HA's multi-targeted effects on the nervous system.

ID: 41963751
Title: Recent Advances in Surface-Engineered Polymeric Nanoparticles for Targeted Paclitaxel Delivery in Breast Cancer Therapy.
Abstract: Breast cancer remains a leading cause of cancer-related mortality worldwide. Paclitaxel (PTX), a first-line chemotherapeutic agent widely used in breast cancer, is widely used due to its potent mechanism of action against rapidly dividing cancer cells. However, its clinical application is significantly hindered by poor solubility, systemic toxicity, and associated adverse effects. Encapsulating PTX in polymeric nanoparticles presents a promising strategy to overcome these limitations by extending drug release, enhancing drug's bioavailability, and enabling active targeting. This review uniquely focuses on recent advances in surface-functionalized polymeric nanoparticles specifically engineered for targeted delivery of PTX in breast cancer therapy and consolidates their translational relevance and next-generation design considerations. Unlike general reviews on polymeric nanocarriers, this article specifically focuses on ligand-functionalized polymeric nanoparticles designed for active targeting of breast cancer cells, integrating biological rationale, receptor specificity, and translational relevance. Surface-engineered polymeric nanoparticles functionalized with ligands such as folic acid, hyaluronic acid, aptamers, and peptides can specifically target overexpressed receptors on cancer cells, including CD44, HER2, and folate receptors. These ligand-receptor interactions facilitate receptor-mediated endocytosis, enhancing intracellular drug delivery while minimizing systemic toxicity. The review highlights key design considerations, including ligand density, nanoparticle architecture, and multifunctionality of next-generation PTX nanocarriers. The development of PTX-loaded polymeric nanoparticles with surface modifications represents a significant advancement in precision drug delivery for breast cancer, addressing key treatment challenges and paving the way for clinical translation.

ID: 41966415
Title: CD44-targeted cyclodextrin-hyaluronic acid nanoparticles carrying gemcitabine and paclitaxel to pancreatic cancer.
Abstract: Pancreatic cancer remains one of the fatal malignancies due to its aggressive nature, late diagnosis, and poor responsiveness to conventional chemotherapy. Overcoming drug resistance and enhancing tumor-specific drug delivery are key challenges in improving therapeutic outcomes. This study aimed to develop actively targeted cyclodextrin-based nanoparticles co-loaded with gemcitabine (GEM) and paclitaxel (PCX) to improve efficacy against pancreatic cancer, particularly in drug-resistant phenotypes. Hyaluronic acid (HA) was used to functionalize the nanoparticles for CD44-mediated active targeting. Comprehensive physicochemical characterization including particle size, zeta potential, drug loading, release profile, and stability was conducted. In vitro studies covered both 2D monolayer and 3D spheroid models of pancreatic cancer, including drug-resistant Panc-1 cells. Apoptosis induction and cholesterol depletion were assessed for mechanistic evaluation. In vivo studies in tumor-bearing mice were performed for efficacy, biodistribution, and systemic safety. All nanoparticle formulations exhibited sub-200 nm diameters, high drug loading efficiencies (>50 %), and sustained release profiles. HA-functionalized nanoparticles demonstrated enhanced cellular uptake, significant cytotoxicity, and apoptosis in both drug-sensitive and resistant cells. In vivo, CD44 targeted dual-drug nanoparticles significantly inhibited tumor growth, showed enhanced intratumoral accumulation, and exhibited no systemic toxicity. These findings suggest that HA-functionalized amphiphilic cyclodextrin nanoparticles co-loaded with GEM and PCX represent a promising strategy to overcome chemoresistance and improve therapeutic efficacy in pancreatic cancer.

ID: 41968043
Title: Targeting the hyaluronic acid-CD44 axis in hepatocellular carcinoma.
Abstract: Hepatocellular carcinoma (HCC) remains a major global health challenge, with rising incidence, frequent development of drug resistance, and limited long-term survival despite advances in systemic therapies. Within the tumor microenvironment, the interaction between hyaluronic acid (HA) and cluster of differentiation 44 (CD44) is linked to tumor progression and therapeutic failure. Accordingly, targeting the HA-CD44 signaling axis represents a promising strategy to overcome resistance. This review highlights potential approaches, including inhibition of HA synthesis, enzymatic HA degradation, CD44 blockade, and HA-based nanocarriers for selective drug delivery, alone or combined with existing therapies. Leveraging HA-CD44 biology may help refine profiling and support the development of more personalized treatments, ultimately enhancing outcomes for HCC patients.

ID: 41968335
Title: Pathogenesis of Adenomyosis: An Integrated Review of Cellular Origins, Molecular Mechanisms, and Intersecting Diseases.
Abstract: Adenomyosis is a prevalent disorder of the archimetra, historically conflated with endometriosis but possessing a unique pathobiological trajectory. This review synthesises current molecular evidence to propose a unified mechanistic framework initiated by tissue injury and repair (TIAR), aberrant stem cell activation, or de novo metaplasia, all of which converge to disrupt the endometrial-myometrial interface disruption (EMID). Following this structural breach, a self-perpetuating 'vicious cycle' is triggered, driven by four interconnected axes: (1) Hormonal Dysregulation, characterised by local hyper-estrogenism, progesterone resistance, and a specific paracrine prolactin loop that drives reactive myometrial hypertrophy; (2) Immune-Hemostatic Crosstalk, where activated platelets and M2-polarised macrophages establish a pro-fibrotic niche via TGF-β1 signalling; (3) Hypoxia and Neuroangiogenesis, where HIF-1α stabilisation orchestrates metabolic reprogramming (Warburg effect) and the pathological sprouting of sensory nerves, underpinning chronic pain; and (4) Epigenetic Fibrosis, driven by the oestrogen-slug-VEGF axis and HDAC-mediated chromatin remodelling leading to epithelial-mesenchymal transition (EMT). Furthermore, we clarify the genetic distinction between adenomyosis and uterine leiomyomas, highlighting their divergent responses to androgen receptor signalling. By elucidating these molecular targets, we discuss emerging non-hormonal therapeutics-including anti-platelet agents and dopamine agonists-offering mechanism-based strategies for fertility preservation.

ID: 41970248
Title: Targeted delivery of lupeol via hyaluronic acid-modified ZIF-8 for anti-hepatic fibrosis therapy.
Abstract: Hepatic fibrosis (HF), a common pathological consequence of chronic liver injury, is driven by the excessive proliferation and activation of hepatic stellate cells (aHSCs). Non-alcoholic steatohepatitis, the inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease, NAFLD), serves as a key driver of the HF process. Although previous studies have found that lupeol can act as an FXR-agonist to ameliorate MASLD through the FXR-SHP pathway, its therapeutic potential is severely limited by drawbacks such as poor solubility, low stability, rapid degradation, insufficient targeting specificity, collectively constrain its therapeutic potential. To overcome these limitations, we developed the HA/Lupeol@ZIF-8-a dual-functional nano-delivery system combining CD44-targeting and pH-responsive drug release. It encapsulates the FXR-agonist lupeol in ZIF-8 framework and is surface-modified with hyaluronic acid to allow for active targeting of CD44-highly-expressing aHSCs. In the acidic-fibrotic microenvironment, ZIF-8 undergoes pH-responsive degradation, enabling precise release of both the lupeol and Zn2+. The released Zn2+ further disrupt glycolysis and facilitate the reversion of aHSCs to quiescent state, thereby synergistically enhancing the anti-fibrotic efficacy. The nanoparticles exhibited a uniform size (125.7 ± 0.16 nm), high stability, pH-dependent drug release and strong CD44-binding affinity, collectively improving lupeol's solubility and targeted delivery. Both in vitro and vivo experiments confirmed that HA/Lupeol@ZIF-8 suppresses fibrotic markers through FXR-SHP activation. This study not only elucidates the anti-fibrotic mechanism of Lupeol but also presents an integrated targeted and microenvironment responsive strategy with considerable potential for clinical translation in the treatment of HF.

ID: 41992318
Title: An all-in-one theranostic platform for enhanced TACE: self-developing embolization with dual-targeted arsenic trioxide delivery.
Abstract: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality. For patients with advanced, unresectable disease, transarterial chemoembolization (TACE) is a recommended first-line locoregional therapy. However, its efficacy is constrained by the inherent limitations of conventional embolic materials-such as non-target embolization, vessel recanalization, and incomplete distal occlusion-and by the low intra-tumoral delivery efficiency of chemotherapeutic agents. Furthermore, the high prevalence of p53 mutations (~ 30%) in HCC drives tumorigenesis and chemoresistance, creating a critical therapeutic gap, especially within the hypoxic tumor microenvironment. To address these multifaceted challenges, we developed an innovative theranostic platform, CHSA/NAT. This system combines a radiopaque, thermosensitive hydrogel (NAT) for precise, image-guided vascular occlusion with CD44-targeted, glutathione (GSH)-responsive chitosan/hyaluronic acid nanomicelles (CHSA), which enable the smart delivery of arsenic trioxide (ATO)-a potent agent with p53-mutant corrective activity. In vitro, ATO demonstrated superior cytotoxicity over doxorubicin against multiple HCC cells under hypoxia. In a p53-mutant PLC/PRF/5 subcutaneous model, CHSA-ATO achieved a tumor inhibition rate of 84.6%, significantly outperforming free ATO and doxorubicin, and effectively modulated apoptotic proteins (downregulating mutant p53/Bcl-2, upregulating Bax). Crucially, superselective administration of CHSA/NAT enabled successful embolization with clear radiological visualization in rat hepatic and renal arteries, demonstrating its precise image‑guided delivery and embolization capability. Most importantly, in an orthotopic rat HCC model, the combined treatment exhibited powerful synergistic efficacy, attaining a remarkable 96% tumor suppression rate and significantly prolonging survival, with a favorable safety profile. This work presents a novel "embolization‑imaging‑targeted chemotherapy" strategy that simultaneously overcomes the key limitations of conventional TACE and ATO delivery, offering a promising and translatable nanoplatform for the effective treatment of advanced HCC.

ID: 42002329
Title: Molecular weight of hyaluronic acid in nanocarriers.
Abstract: Hyaluronic acid (HA) is widely used in nanomedicine owing to its biocompatibility, receptor-targeting ability, and structural versatility. Among the key design parameters of HA-based nanocarriers, molecular weight (MW) critically influences biological performance; yet the optimal MW remains controversial. Although higher MW is often assumed to enhance CD44 binding and targeting efficiency, evidence indicates that its effects are multidimensional, context-dependent, and frequently non-linear. This review systematically examines how the MW of HA regulates cellular uptake, active targeting, drug solubilization, release kinetics, biodegradation, immunomodulation, and translational potential. At the cellular level, HA MW modulates multivalent CD44 engagement and receptor clustering, often producing a bell-shaped relationship with internalization efficiency. At the tissue level, MW affects tumor accumulation through competing influences on receptor avidity, nanoparticle size, and systemic clearance. Lower-MW HA generally promotes barrier penetration, cellular uptake, and pro-inflammatory responses, whereas higher-MW HA enhances stability, anti-inflammatory signaling, and circulation time but may reduce uptake due to steric hindrance. Overall, optimal MW selection depends on nanocarrier design, disease context, and dominant biological barriers. This review provides a mechanistic framework to guide rational MW selection in next-generation HA-based nanotherapeutics.

ID: 42005465
Title: Kidney-targeted drug delivery: from physiological mechanisms to precision therapeutics.
Abstract: Chronic kidney disease (CKD) and acute kidney injury (AKI) remain critical global health challenges, yet effective pharmacotherapies are severely limited by poor renal bioavailability and off-target systemic toxicity. Overcoming these obstacles requires a deep integration of renal physiopathology with advanced drug delivery engineering. This review provides a comprehensive analysis of the mechanisms governing kidney-targeted drug delivery. We first dissect the unique physiological barriers that dictate renal drug disposition, including the size- and charge-selective glomerular filtration barrier ("the sieve") and the high-capacity reabsorption machinery of the proximal tubule (e.g., megalin-mediated endocytosis). Subsequently, we elucidate the pathological alterations in the "fibrotic niche", highlighting emerging therapeutic targets such as the upregulated CD44 receptor and specific integrins on myofibroblasts. Based on this understanding, we systematically categorize current delivery strategies into two paradigms: (1) Passive Targeting, which exploits physicochemical properties (e.g., 75-100 nm size range for mesangial sequestration); and (2) Active Targeting, which utilizes ligand-receptor precision to direct carriers to the tubular epithelium (via megalin or transporters) or the fibrotic microenvironment (via hyaluronic acid or RGD [Arg-Gly-Asp]). Finally, we discuss the challenges of clinical translation, including interspecies differences and long-term nanotoxicology, and outline future directions in bio-inspired vectors and stimuli-responsive logic-gated systems. Ultimately, the seamless integration of these modular delivery platforms with patient-specific molecular signatures heralds a new era of precision nephrology, moving beyond systemic management toward site-specific interventions that may fundamentally reverse the progression of renal failure.

ID: 42011733
Title: Preliminary study on targeted nanoparticles co-loaded with piperine and paclitaxel prodrug for ovarian cancer treatment.
Abstract: Combination chemotherapy incorporating natural products has emerged as an effective strategy to enhance anticancer efficacy while reducing systemic toxicity. Based on this, our study report a targeted, stimuli-responsive nanoparticle system for the co-delivery of paclitaxel (PTX) and piperine (PIP) to achieve synergistic ovarian cancer therapy. PTX was chemically conjugated to polyamidoamine (PAMAM) dendrimers via a glutathione (GSH)-sensitive disulfide linkage, while PIP was physically encapsulated within the hydrophobic core of PAMAM. Hyaluronic acid (HA) was subsequently electrostatically assembled onto the nanoparticle surface to enable CD44-mediated tumor targeting. The resulting nanoparticles exhibited a uniform spherical morphology with an average diameter of approximately 145 nm and demonstrated dual responsiveness to elevated GSH and acidic pH conditions characteristic of the tumor microenvironments. In vitro and in vivo antitumor studies revealed that the co-delivery system significantly enhanced cytotoxicity and apoptosis through synergistic PTX/PIP activity compared with monotherapy. In addition, HA modification markedly improved cellular uptake and tumor accumulation, leading to effective tumor growth inhibition in vivo with reduced systemic toxicity. In conclusion, this study highlights a rationally engineered nanocarrier integrating active targeting and stimuli-responsive release, offering a promising materials-based strategy for synergistic ovarian cancer therapy.

ID: 42055152
Title: Preparation of CPD12C15 hyaluronic acid nanoparticles, a novel glycolytic inhibitor and preliminary pharmacologic study on anti-pancreatic cancer.
Abstract: Pancreatic cancer (PC) is one of the most insidious malignant tumors with aggressive metastasis and ineffective treatments. Although gemcitabine (GEM) is the gold standard for PC, the acquired resistance and severe myelosuppression limit clinical utility. It has been found that abnormal aerobic glycolysis may be responsible for drug resistance in PC. Disulfiram (DSF), a commonly used anti-alcoholic drug, possesses potent anti-tumor activity combined with copper. Nevertheless, poor water solubility and neurotoxicity restrict clinical applications. Therefore, our group modified the structure of DSF and synthesized a novel compound CPD12C15, which exhibited stronger anti-tumor activity and lower neurotoxicity than DSF. Nanoparticles with excellent release properties, modified with hyaluronic acid (HA) targeting CD44, which is highly expressed on pancreatic cells, can evade the removal of natural defense system and enhance tumor-targeting ability. Herein, CPD12C15 was loaded into HA-modified PLGA nanoparticles (HPC-NP) in order to improve the sustained release properties and active targeting ability. Our research revealed that CPD12C15 combined with Cu (HPC-NP/Cu) could inhibit tumor proliferation, migration, invasion and induce apoptosis by suppressing the aerobic glycolysis pathway, which further inhibited cell stemness and drug resistance in vivo and in vitro, suggesting that it may be a potential strategy for PC treatment.

ID: 42093737
Title: Localized delivery of hyaluronic acid-doxorubicin from a surgical paste for post-operative glioblastoma treatment.
Abstract: Glioblastoma stem cells (GSCs) and residual tumor cells - which resist conventional therapies, drive disease recurrence, and contribute to the formation of an immunosuppressive tumor-immune microenvironment (TIME) - represent a crucial barrier to the effective treatment of post-operative glioblastoma, the most aggressive and lethal primary brain tumor in adults. The cavity left after tumor resection represents a valuable opportunity to deliver therapeutics locally via the placement of conformable scaffolds for the immediate chemotherapeutic targeting of GSCs and residual glioblastoma cells. We hypothesized that Surgiflo™, a moldable, FDA-approved gelatin-based hemostatic paste, could serve as a dual-purpose platform that minimizes postoperative bleeding and functions as a conformable, local, and sustained drug-delivery system. We incorporated a pH-sensitive designed hyaluronic acid-doxorubicin polymer-drug conjugate (HA-DOX) into the Surgiflo™ matrix, exploiting HA's selective affinity for CD44 (highly expressed by both GBM and GSCs) and promoting the depletion of GBM and GSCs via immunogenic cell death (ICD)-inducing properties of DOX. In vitro studies of HA-DOX-containing paste confirmed enhanced HA-DOX uptake in GSC-enriched models, improved ICD induction in GBM cells, favorable biocompatibility, and sustained drug release. In vivo evaluations revealed that intracavitary implantation of the HA-DOX-containing paste significantly prolonged the median survival of treated mice compared to the untreated group (37 days vs 25 days, respectively) and modulated the glioblastoma-associated TIME, resulting in a 44% reduction in GSC levels and a significant increase in CD8+ T cell levels (∗p < 0.5), compared to resected mice. Embedding HA-DOX within Surgiflo™ offers a promising strategy for localized, sustained delivery of chemotherapeutics to the resected cavity, with the potential to improve therapeutic outcomes and minimize systemic toxicity in postoperative glioblastoma treatment.

ID: 42169331
Title: Representative probiotic extracellular vesicles engineered with modified hyaluronic acid and tea polyphenol for enhancing bioactive stability and targeted cellular delivery.
Abstract: Curcumin (Cur) and anthocyanin (Ant) are typical plant-derived bioactives with promising biological benefits, but poor stability and bioavailability limit their applications. To address these challenges, we engineered a targeted co-delivery platform by systematically comparing two representative, probiotic-derived extracellular vesicle carriers: outer membrane vesicles (OMVs) from Escherichia coli Nissle 1917 and extracellular vesicles (EVs) from Lactobacillus plantarum. Encapsulation efficiency (EE) of Cur was 41.6% for OMVs and 35.9% for EVs, whereas EE of Ant was 25.4% and 24.6%, respectively. Both vesicle types were further synergistically functionalized with specifically acylated epigallocatechin palmitate (EGCp) and octenyl succinic anhydride-grafted hyaluronic acid (OSA-HA). The incorporation efficiency of EGCp was 27.2% for OMVs and 37.3% for EVs. The self-assembly process yielded composite nanovesicles with a reduced particle size (OMVs: from 165.6 nm to 143.2 nm; EVs: from 156.8 nm to 120.8 nm) and a more negatively charged surface (from -20.8 mV to -37.5 mV for OMVs; from -18.3 mV to -35.3 mV for EVs) compared to their native counterparts, indicating improved colloidal properties. In addition, both engineered nanovesicles effectively protected the encapsulated bioactives, significantly enhancing their stability against simulated gastrointestinal digestion and oxidative stress. For example, the retention of Cur under oxidative conditions increased from 24.2% in unmodified OMVs to 69.1% in the optimized formulation within 2 h. Cellular uptake assays confirmed the OSA-HA coating achieved targeted delivery to inflammatory macrophages, with OSA-HA-modified OMVs exhibiting higher cellular internalization (75.4% at 12 h) than similarly modified EVs (61.8% at 12 h). While both types of functionalized nanovesicles enhanced intracellular antioxidant activity to a similar extent, the OMV-based system demonstrated superior suppression of pro-inflammatory mediators (NO, TNF-α, and IL-6) in mitigating lipopolysaccharide (LPS)-induced cell damage. This comparative study establishes a biocompatible probiotic-based colloidal platform, demonstrating the potential of two selected engineered probiotic vesicles and functionalized polysaccharides for the encapsulation and targeted cellular delivery of sensitive bioactive compounds.

ID: 42202863
Title: Hyaluronic acid-based biomaterials for the treatment of osteosarcoma and postoperative bone repair.
Abstract: Osteosarcoma is a common malignant bone tumor in adolescents. Clinical treatments face major challenges, including postoperative recurrence, refractory bone defects, and inadequate targeting of chemotherapeutic drugs. Hyaluronic acid (HA), a natural component of the human extracellular matrix, serves as an ideal material for integrating osteosarcoma therapy and postoperative bone regeneration, attributed to its unique properties including CD44-mediated tumor targeting, tumor microenvironment-responsive degradation, excellent biocompatibility, and functional tunability. This review summarizes recent advances in HA-based materials for osteosarcoma therapy. HA acts as a versatile carrier for chemotherapeutic drugs (e.g. doxorubicin (DOX), cisplatin (CDDP)) and therapeutic nucleic acids, via nanoparticles, liposomes, or hydrogels. These carriers enhance intratumoral drug accumulation, reduce systemic toxicity, evade immune recognition, and facilitate intracellular drug delivery. Incorporating bioactive glass or magnesium-based nanomaterials into HA constructs a multifunctional therapy-regeneration system, which simultaneously inhibits tumor growth and promotes bone regeneration, addressing postoperative bone defects. Furthermore, we analyze key obstacles to clinical translation, such as rapid degradation, insufficient hydrogel mechanical strength, and poor sterilization compatibility, and propose solutions including chemical cross-linking and composite modification. These insights provide valuable guidance for the precise design of HA-based biomaterials and their clinical translation, aligning with the demand for therapy-repair integration in regenerative medicine.

ID: 42208268
Title: Hyaluronic acid-based multifunctional biomaterials: Cartilage/skin regeneration, vitreous substitutes, and drug delivery systems.
Abstract: Hyaluronic acid (HA) is a naturally occurring endogenous mucopolysaccharide and also a major component of the extracellular matrix (ECM). Due to its biocompatibility, biodegradability, non-toxicity and cluster of differentiation-44 (CD44) receptor-mediated targeting, it is widely used as a medical material in the fields of tissue engineering, regenerative medicine, and drug delivery systems (DDS). Herein, the latest research on HA-based medical materials over the past 5 years is systematically reviewed, focusing on the frontier advances on the utilization of HA and its derivatives in cartilage/skin regeneration, vitreous substitutes, and DDS. HA-based hydrogels can be used for articular cartilage regeneration by promoting the proliferation and differentiation of chondrocytes and the formation of ECM. As a vitreous substitutes, HA-based hydrogels have similar properties to natural vitreous humor. In the field of skin regeneration, HA has the ability to accelerate wound healing and construct complex skin substitutes. For DDS, different forms such as HA-drug conjugate nanoparticles (NPs), HA-surface modified NPs, nanomicelles, and hydrogels can be applied. The preparation methods, delivery mechanisms, in vitro and in vivo evaluations, and advantages of DDS are explained. Additionally, the challenges and future perspectives of HA-based medical materials are also discussed.

ID: 42211882
Title: M1 macrophage-targeted engineered ginseng stems and leaves-derived extracellular vesicles delivery system for alleviating rheumatoid arthritis.
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, oxidative stress damage and joint destruction. Current treatments often face challenges including limited targeting efficacy and systemic side effects. To develop a novel targeted therapy for RA, this study constructed a functionalized extracellular vesicle (EV) system by engineering ginseng stems and leaves-derived EVs with hyaluronic acid (HA) modification and curcumin (Cur) loading (Cur@EVs-PH). Structurally, the EVs-PH drug-loaded nanoplatform integrates the remarkable anti-inflammatory and antioxidant properties of EVs with the prolonged circulation capacity conferred by PEG. This design further capitalizes on the targeting ability of HA, thereby providing a robust structural foundation for the efficient delivery of therapeutics to disease sites. Our results demonstrated that the designed system achieved enhanced inflammatory targeting through CD44 receptor-mediated accumulation and exhibited potent anti-inflammatory and antioxidant activities. In the collagen-induced arthritis model, Cur@EVs-PH significantly alleviated joint swelling, reduced pathological scores and normalized immune organ indices. Mechanistic studies revealed that the therapeutic effects were mediated through suppression of pro-inflammatory cytokines and promotion of macrophage M2 polarization. This integrated strategy combining natural EVs, targeted modification and active drug loading provides a promising platform for the treatment of RA and other inflammatory diseases.

ID: 42218212
Title: Dental pulp-derived mesenchymal stem cells reduce lesion progression in a rat model of endometriosis.
Abstract: Endometriosis is a chronic, estrogen-dependent inflammatory disease sustained by aberrant angiogenesis and progressive fibrosis. We evaluated the therapeutic efficacy of human dental pulp-derived mesenchymal stem cells (DP-MSCs) in a surgically induced rat endometriosis model. Twenty-eight adult female Wistar rats were randomized (n = 7/group) to sham group (G1), untreated endometriosis-group (G2), single-dose DP-MSCs-group (G3) (2 × 106 cells intraperitoneally on day 28) and double-dose DP-MSCs-group (G4) (2 × 106 cells on days 28 and 35). Endometriosis was induced by autologous uterine tissue implantation onto the peritoneal wall and allowed to establish for 28 days; treatment effects were assessed 7 days after the final DP-MSCs dose. Serum and peritoneal TNF-α, IL-6, VEGF, and CA-125 were quantified; lesions were evaluated by semi-quantitative histopathology and fibrosis grading and by immunohistochemistry for CA-125, VEGF, type I collagen (Col1), and TNF-α. Untreated endometriosis showed increased systemic TNF-α (p = 0.0207) and IL-6 (p = 0.0003) and marked peritoneal elevations versus sham (all p < 0.0001). DP-MSCs treatment significantly reduced peritoneal TNF-α and IL-6 in both regimens (each p < 0.0001 vs untreated) and decreased peritoneal VEGF, with greater suppression after double dosing (p = 0.0100 between regimens). Double dosing produced stronger systemic TNF-α suppression (p = 0.0027 vs untreated). Histopathology and fibrosis improved, most prominently with double dosing (both p < 0.0001), accompanied by reduced CA-125, VEGF, Col1 and TNF-α immunoreactivity (CA-125 and TNF-α, p < 0.0001). DP-MSCs effectively resolve the hallmark pathological features of endometriosis in a dose-dependent manner. By synergistically targeting inflammatory, angiogenic, and fibrotic pathways, this cell-based strategy offers a potent, disease-modifying approach for clinical management.

ID: 42235198
Title: Multifunctional self-assembled nanoparticles loaded into immunomodulatory microneedles for synergistic therapy of psoriasis.
Abstract: Psoriasis is an immune-mediated inflammatory skin disease that currently lacks safe and effective transdermal therapies capable of multi-target action. In this study, hyaluronic acid (HA) and glycyrrhetinic acid (GA) were separately conjugated to D-alpha tocopherol acid polyethylene glycol succinate (TPGS), which subsequently self-assembled into nanoparticles (HA/GA-NPs). Bletilla striata polysaccharide (BSP) and HA were employed as the microneedle matrix to fabricate soluble microneedles incorporating the nanoparticles (HA/GA-NPs-MNs). This strategy combined the CD44-targeting capability and anti-inflammatory activity of the nanoparticles with the immunomodulatory function and efficient penetration-enhancing ability of the BSP-based microneedles, thereby achieving synergistic therapeutic effects against psoriasis. In vitro studies demonstrated that the CD44-targeting capability of HA/GA-NPs enhanced cellular uptake, reduced intracellular ROS expression, and suppressed the inflammatory proliferation of HaCaT cells. Concurrently, BSP and HA/GA-NPs synergistically promote M2 polarization in RAW264.7 cells while suppressing the production of NO and proinflammatory factors IL-6, TNF-α, and IL-1β. Furthermore, HA/GA-NPs-MNs enhanced drug accumulation and skin penetration, enabling efficient delivery into the deeper skin layers. During in vivo studies, the system was observed to significantly enhance immune regulation and demonstrated the strongest efficacy in suppressing psoriatic inflammatory infiltration. The primary therapeutic mechanism of HA/GA-NPs-MNs against psoriasis involved the blockade of STAT3 phosphorylation to inhibit IL-23 signaling and downstream IL-17 release. The biosafety assessment confirmed high dermal and hemocompatibility of the system. This work presented a novel integrated platform of multifunctional self-assembled nanoparticles and immunomodulatory microneedles for the topical treatment of psoriasis.

ID: 42250822
Title: A charge-reversible hyaluronic acid prodrug nanoplatform for synergistically enhanced tumor-targeted doxorubicin delivery.
Abstract: Conventional nanocarriers often face challenges of insufficient tumor specificity and poor cellular internalization. To overcome these limitations, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. Doxorubicin (DOX) was covalently conjugated to oxidized HA via a pH-sensitive imine bond, while a charge-reversal polymer (PLL-DMMA) was grafted onto the HA backbone. This design enables CD44-mediated active targeting toward cancer cells. Crucially, the nanoplatform exhibits a smart charge-reversal characteristic: maintaining a negative surface charge (-32.8 mV) at physiological condition (pH 7.4) for extended circulation, while switching to positive (+16.5 mV) in the acidic tumor microenvironment (pH 6.5) to enhance cellular uptake. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. The release profile showed high stability at pH 7.4 (<5% release in 5 days) and rapid drug release at endo/lysosomal pH (61.6% at pH 5.0). Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC50 values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery.

ID: 42346610
Title: Epigenetics, Oxidative Stress, and the Microbiome in Endometriosis: Toward an Integrated Mechanistic Framework for Precision Medicine.
Abstract: Endometriosis (EM) is a chronic, estrogen-dependent inflammatory disorder affecting approximately 6-10% of women of reproductive age in the general population and remains a major cause of chronic pelvic pain and infertility. High recurrence rates and enduring symptoms despite current treatments underscore the need for a more thorough understanding of its intricate biology. There is growing evidence that the interaction among oxidative stress (OS), microbiome dysbiosis, and epigenetic dysregulation contributes to immunological activation, hormonal imbalance, and the persistence of ectopic lesions. Important disease mechanisms, such as progesterone resistance, inflammatory signaling, and aberrant cellular proliferation, are influenced by epigenetic changes, which include aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs. Simultaneously, high levels of reactive oxygen species (ROS) reinforce lesion survival and chronic inflammation by promoting angiogenesis, fibrosis, and tissue damage. Changes in the microbiome also affect immunological responses, oxidative balance, estrogen metabolism, and epigenetic control, indicating the existence of interrelated pathogenic loops. This narrative review presents an integrated mechanistic framework for endometriosis, summarizing the available data that connect these pathways. Furthermore, the growing implications of non-invasive biomarkers and precision medicine techniques highlight the potential for improved diagnosis, disease classification, and targeted treatment approaches.

ID: 42401301
Title: Dual-trigger hyaluronic acid nanoprodrug incorporating a 2-nitrobenzenesulfonyl linker for CD44-targeted and glutathione-responsive drug delivery.
Abstract: Selective intracellular activation of anticancer agents while minimizing toxicity toward non-target tissues remains a major challenge in drug delivery systems (DDSs) and prodrug design. In this study, we designed a hyaluronic acid-based prodrug system, HA-Ns-Dox, that integrates receptor-mediated cellular uptake with intracellular glutathione (GSH)-responsive activation. A doxorubicin (Dox) prodrug modified with a 2-nitrobenzenesulfonyl (Ns) group was synthesized and subsequently conjugated to hyaluronic acid (HA) via click chemistry to generate HA-Ns-Dox with both CD44-targeting capability and GSH-responsive activation properties. HA-Ns-Dox formed stable nanosized assemblies in aqueous solution and exhibited high stability under low-GSH conditions mimicking extracellular environments, whereas concentration-dependent activation of Dox was observed under high-GSH conditions mimicking intracellular reductive environments. In vitro studies demonstrated that HA-Ns-Dox was selectively internalized into the CD44-high human breast cancer cell line MDA-MB-231, accompanied by intracellular prodrug activation and nuclear accumulation of Dox. In contrast, cellular uptake and activation were minimal in the CD44-low cell line MCF-7, and cytotoxicity was significantly suppressed even at high concentrations. Cytotoxicity studies further revealed that HA-Ns-Dox exhibited significant antiproliferative activity in CD44-high cells while substantially reducing toxicity toward non-target cells. Collectively, these findings demonstrate the potential of combining CD44-targeted delivery with GSH-responsive prodrug activation to improve cancer cell selectivity.

ID: 42401307
Title: Steroidal alkaloids as multi-target therapeutics for the treatment of endometriosis.
Abstract: Endometriosis is a chronic inflammatory disease characterised by ectopic endometrial tissue, progressive fibrosis and chronic pain, with a pathogenesis that goes beyond oestrogen dependence. The central question this review seeks to answer is: are steroidal alkaloids - nitrogenous plant-derived steroids with a unique structure - a mechanistically sensible, non-hormonal alternative that can simultaneously target the inflammatory, fibrotic and epigenetic drivers of endometriotic lesion persistence, while preserving fertility and avoiding systemic hormonal suppression? A growing body of evidence points to non-hormonal molecular networks including immune dysregulation, angiogenesis, and resistance to apoptosis as drivers of lesion persistence. These molecular disturbances are associated with treatment resistance and limit the long-term efficacy of hormone-based therapies. This review synthesises recent mechanistic advances that describe the non-hormonal signalling pathways that maintain endometriotic lesions, with a specific emphasis on NF-κB-mediated sterile inflammation, inflammasome activation, PI3K/Akt/mTOR-dependent survival signalling, Hedgehog-driven fibrosis and epigenetic repression of progesterone receptor expression. Steroidal alkaloids are critically reviewed as multitarget modulators suppressing inflammatory signalling, inhibiting invasive and fibrotic remodelling, and restoring apoptotic sensitivity in this pathophysiological context, without direct systemic oestrogen deprivation. Structural determinants of steroidal alkaloid activity, including glycosylation status, nitrogen topology and configuration of the steroidal scaffold, are discussed in the context of pathway selectivity, pharmacokinetics and toxicity. Preclinical in vitro and in vivo evidence is critically reviewed in the context of key translational limitations such as bioavailability constraints, narrow therapeutic index and teratogenic risk from developmental pathway inhibition. This review highlights steroidal alkaloids as a mechanistically rational, non-hormonal approach to target lesion persistence and fibrosis in endometriosis, integrating molecular, pharmacological and structural insights, and outlines the major hurdles that must be overcome for clinical translation. The main objective of this review is to address a specific unanswered question: can steroidal alkaloids with their multitarget pharmacology offer a biologically coherent, non-hormonal strategy for the treatment of endometriosis that goes beyond oestrogen deprivation to target the molecular machinery of lesion survival, fibrosis and immune dysregulation. This question is addressed by reviewing the nonhormonal signalling networks that support ectopic lesions, the structural and pharmacokinetic properties of steroidal alkaloids that are relevant to these pathways, and the translational challenges that need to be addressed for clinical translation.

ID: 42418937
Title: Tokishakuyakusan suppresses endometriosis and may be associated with improved fertility during attempts to conceive: A mouse model study.
Abstract: Tokishakuyakusan (TSS), a traditional Japanese Kampo medicine, is known for its anti-inflammatory and anti-angiogenic properties. This study examined the effects of TSS on fecundity and endometriosis-like lesions during pregnancy in a murine model of endometriosis. Endometriosis model mice were divided into four groups: Sham operation + control diet (Sham/Cont), Sham operation + 3% TSS diet (Sham/TSS), Endometrium dispersion + control diet (End/Cont), and Endometrium dispersion + 3% TSS diet (End/TSS). Mating was initiated one day after surgery, and females were sacrificed on postpartum day 3. Endometriosis-like lesion size, inflammatory cytokine levels, and reproductive outcomes were evaluated. Time to delivery tended to be shorter in the End/TSS group than in the End/Cont group (median: 23.5 vs. 27 days), although the difference was not statistically significant. The maximum lesion diameter in the End/TSS group was significantly smaller compared to the End/Cont group (median: 4.54 mm vs. 7.76 mm, p = 0.044). Concentrations of the inflammatory cytokines MIP-3α and IL-17A were significantly lower in the End/TSS group (MIP-3α: 14.54 [12.91, 18.98] vs. 25.26 [16.81, 48.58] pg/mg protein, p = 0.019, IL-17A: 10.00 [9.05, 18.76] vs. 19.06 [16.75, 82.81] pg/mg protein, p = 0.019). TSS administration reduced endometriosis-like lesion size and was associated with suppression of Th17-related inflammatory mediators in a murine model of endometriosis. Consequently, the administration of TSS tended to shorten the time to pregnancy. These findings suggest that TSS may exert immunomodulatory effects within endometriosis lesions and could represent a potential non-hormonal therapeutic approach during the peri-conceptional period.

ID: 42421100
Title: The endometriosis-adenomyosis spectrum: shared pathophysiology and microenvironment-driven disease divergence.
Abstract: Endometriosis and adenomyosis are common gynecologic disorders associated with dysmenorrhea, chronic pelvic pain, and infertility. Although they share several molecular features, the mechanisms by which endometrium-derived tissues develop distinct pathological phenotypes in different tissue environments remain incompletely understood. This review summarizes shared and divergent pathogenic mechanisms, focusing on lesion-specific microenvironments. This narrative review was based on a PubMed literature search from the year of the first publication through December 2025 using terms related to endometriosis, adenomyosis, mitochondrial function, oxidative stress, fibrosis, mechanical stress, and calcium signaling. Both disorders develop in the context of repetitive tissue injury, estrogen-dependent repair responses, chronic inflammation, oxidative stress, and mitochondrial dysfunction. However, differences in lesion location and microenvironment appear to drive distinct pathological phenotypes. In superficial peritoneal endometriosis and ovarian endometrioma, mitochondrial adaptation primarily supports hypoxia tolerance, oxidative stress responses, angiogenesis, cellular survival, and metabolic reprogramming. In contrast, deep infiltrating endometriosis and adenomyosis are characterized by fibrosis, extracellular matrix remodeling, tissue stiffening, and adaptation to mechanical stress. In adenomyosis, mitochondrial regulation of calcium homeostasis, smooth muscle contractility, reactive oxygen species production, and TGF-β-related fibrotic signaling may play important roles in disease progression. We propose a proliferation-fibrosis divergence model in which common pathogenic stimuli are integrated through mitochondria-dependent responses to distinct local microenvironments. Mitochondria may act as central regulators linking hypoxic adaptation, inflammation, metabolism, fibrosis, and mechanotransduction, thereby influencing whether disease progression favors proliferative expansion or fibrotic remodeling. This framework may provide a basis for future mechanism-based precision therapeutic strategies.

ID: 42435660
Title: Molecular glycoengineering of carbohydrate-functionalized nanocarriers for receptor-mediated targeted drug delivery in cancer.
Abstract: Carbohydrate-functionalized nanocarriers have moved from a decorative surface-modification concept to a molecular drug-delivery strategy in which glycan ligands, polysaccharide shells and synthetic glycopolymers are engineered to negotiate tumor recognition, receptor clustering, endocytosis, intracellular trafficking and stimulus-triggered release. The field is scientifically attractive because cancer cells and tumor-associated stromal cells remodel their glycocalyx, overexpress selected carbohydrate-recognizing receptors and display altered metabolic demand; however, the translation of glycoengineered nanomedicine remains limited by low tumor delivery efficiency, heterogeneous receptor density, competitive off-target uptake by liver and macrophages, batch-to-batch variation in ligand density and insufficient quantitative reporting. This review re-frames carbohydrate-mediated cancer drug delivery as an evidence-weighted design problem. It integrates receptor-density data, particle-size boundaries, ligand-density ranges, release-rate targets, in vitro uptake metrics, pharmacokinetic endpoints and preclinical efficacy readouts into a quantitative framework. Special attention is given to hyaluronic acid-CD44, galactose/GalNAc-ASGPR, mannose-CD206, sialylated glycan-siglec/selectin, beta-galactoside-galectin and glucose/GLUT-related approaches, with emphasis on what the available data can and cannot prove. The central conclusion is that molecular glycoengineering is most defensible when carbohydrate chemistry is linked to measurable receptor engagement, competitive inhibition, uptake kinetics, intracellular drug exposure and statistically stronger antitumor benefit rather than to generic claims of active targeting. The framework explicitly links anomeric configuration, glycosidic linkage, branching, sulfation/acetylation, epitope display and glycan-protein hydration to receptor-specific pharmacological outcomes, thereby shifting the emphasis from general nanomedicine performance to carbohydrate structure-activity relationships required for a carbohydrate-chemistry readership.

ID: 42493250
Title: CD44-Targeted Delivery of Melittin and Celecoxib via Hyaluronic Acid-Coated Polymersomes for Synergistic Anti-Inflammatory Therapy.
Abstract: Activated macrophages are key effector cells in inflammatory diseases, but the therapeutic use of membrane-active agents such as melittin (MEL) is limited by nonspecific cytotoxicity and hemolysis. Here, we developed a hyaluronic acid (HA)-coated MEL-based polymersome (PMHA) for CD44-targeted codelivery of MEL and celecoxib (CXB). MEL was incorporated into the vesicular membrane, whereas CXB was loaded into the hydrophobic domain. PMHA showed a hydrodynamic diameter of 265.5 ± 1.6 nm, a zeta-potential of -21.14 ± 1.1 mV, a CXB encapsulation efficiency of 70.81 ± 4.18%, and a drug loading capacity of 12.87 ± 1.92%. In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, anti-CD44 antibody blocking reduced Alexa Fluor 647-labeled PMHA uptake by approximately 37.5%, supporting HA-CD44-mediated internalization. PMHA reduced MEL-associated cytotoxicity and hemolytic activity and enabled pH-responsive CXB release. Codelivery of MEL and CXB suppressed cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression, with combination index (CI) values of 0.48 and 0.67, respectively. These findings support further evaluation of PMHA as a macrophage-targeted anti-inflammatory nanoplatform.

ID: 42568566
Title: Innovative hyaluronic acid-decorated quatsomes for enhanced renal targeting: design, optimization and in-vivo biochemical and nephroprotective assessments.
Abstract: The kidney plays a critical role in metabolite excretion, fluid regulation, and homeostasis, yet remains highly vulnerable to structural and functional disorders. Kidney diseases represent a major global health burden, often progressing to chronic complications due to the limited efficacy and poor selectivity of conventional therapies, which are frequently associated with systemic toxicity. Accordingly, the development of targeted drug delivery systems is essential to improve therapeutic outcomes. In this study, advanced quatsomes were developed as a kidney-targeted nanosystem to enhance the delivery of curcumin, a natural polyphenolic compound with potent antioxidant and nephroprotective properties. The system was composed of di-dodecyl-dimethyl-ammonium bromide (DDAB), cholesterol, limonene, hyaluronic acid (HA) and surfactants, and was fabricated using the ethanol injection method. A 23 factorial design was employed to optimize formulation variables, including DDAB:cholesterol ratio, limonene:drug ratio, and surfactant concentration. The optimized formulation (desirability = 0.950) exhibited high entrapment efficiency (87.80%), nanosized vesicles (120.55 nm), and a positive surface charge (+38.30 mV). Transmission electron microscopy confirmed spherical morphology, while in-vitro release studies demonstrated a biphasic profile. The formulation also showed good physicochemical stability and enhanced antioxidant activity. Mechanistically, passive targeting via nanoscale size and cationic charge facilitated interaction with the glomerular filtration barrier and mesangial uptake, while limonene improved vesicle deformability. HA functionalization further enabled CD44-mediated active targeting. In vivo, the optimized system significantly reduced serum creatinine and blood urea nitrogen levels in a cisplatin-induced nephrotoxicity model, with histological evidence of renal protection. Overall, the developed quatsomes demonstrate promising potential as an efficient renal-targeted nanocarrier.

ID: 42568871
Title: Lactate metabolism regulation enhances cuproptosis to activate antitumor immunity: Synergistic therapy of hyaluronic acid nanomicelles delivering lactate oxidase/copper-doped carbon dots combined with α-PD-L1 inhibits distant tumors.
Abstract: To address the core issue of low clinical response rates (10%-30%) to α-PD-L1 immune checkpoint blockade therapy, this study targeted the immunosuppressive bottleneck mediated by lactate accumulation in the tumor microenvironment (TME). A targeted drug delivery system (HLC) was constructed using hyaluronic acid (HA) nanomicelles co-loaded with lactate oxidase (LOX) and copper-doped carbon dots (CuCDs). Combined with α-PD-L1, a synergistic antitumor strategy integrating lactate metabolic regulation, cuproptosis, and immune activation was established. HLC achieves targeted accumulation through specific binding between HA and CD44 receptors on tumor cells. It directionally releases LOX and CuCDs in the acidic TME via pH-responsive properties. LOX efficiently clears lactate and elevates pH, blocking the HIF-1α/PD-L1 pathway to reverse immunosuppression. It also generates H2O2 in situ to provide substrates for Cu-mediated Fenton-like reactions, enhancing cuproptosis. In vitro experiments confirm that HLC promotes dendritic cell maturation and drives M2-type macrophage polarization toward the M1 phenotype. In vivo studies using CT26 tumor-bearing mouse models show that HLC combined with 808 nm laser and α-PD-L1 significantly inhibits primary and distant tumor growth. It remodels the antitumor immune microenvironment with favorable biosafety. This study elucidates the synergistic mechanism between lactate metabolic regulation and cuproptosis, establishes an association between lactate level and cuproptosis sensitivity, and provides a novel strategy and experimental basis for combined cancer immunotherapy with important clinical translation value.

ID: 42586120
Title: Hyaluronic acid-based nanocarriers for cancer therapy: molecular design, biointerface mechanisms, and translational challenges.
Abstract: Hyaluronic acid (HA) has emerged as a versatile structural material and targeting ligand within cancer drug delivery systems (DDSs) and nanomedicine applications, owing to its biodegradability, tunable chemistry, and strong affinity for CD44 and related receptors. This review examines studies published from 2019 to 2026, with emphasis on high-quality research in leading journals, and connects the structural parameters of HA with quantitative drug delivery efficiency and therapeutic performance. The major HA-based carrier systems, including micelles, liposomes, polymeric nanoparticles, metal-organic frameworks, and electrospun fiber systems, are critically analyzed in relation to HA molecular weight, degree of substitution, and ligand density, as well as their effects on hydrodynamic size, zeta potential, colloidal stability, and cellular uptake. Across these studies, the most effective designs generally feature nanoscale dimensions that balance circulation and tumor penetration while maintaining near-neutral or slightly negative surface potentials to minimize nonspecific interactions, highlighting the importance of rational physicochemical design for improving therapeutic performance.
Quantitative models of drug release, together with in vitro potency indices such as half-maximal inhibitory concentration (IC50) and combination index, as well as in vivo pharmacokinetic and efficacy indicators including half-life, area under the curve (AUC), and tumor-to-organ ratio, demonstrate how the configuration of HA influences therapeutic selectivity and systemic safety. To improve the rigor and reproducibility of future studies, this review further proposes a concise reporting framework integrating materials characterization, biological evaluation, and animal experiments, while highlighting the current limitations in standardization and cross-study comparability.
In conclusion, this review summarizes the current design principles of HA-based nanocarriers while critically discussing the remaining challenges, including CD44 heterogeneity, microenvironmental competition, and the lack of standardized evaluation strategies. Together, these perspectives provide practical guidance for the rational design, comparative evaluation, and clinical translation of next-generation HA-based nanocarriers.&#xD.

ID: 42602668
Title: Enzyme/Reactive Oxygen Species-Dually Activated Hyaluronic Acid Nanocarriers Enable Celastrol Delivery for Site-Specific Therapy of Inflammatory Bowel Diseases and Colorectal Cancer.
Abstract: Conventional oral nanocarriers for intestinal diseases rely on single-responsive mechanisms and target a single pathological stage, failing to address the inflammation-carcinoma continuum. Celastrol (Cel)'s oral translation is limited by poor bioavailability and lack of lesion-specific targeting. To overcome these barriers, we constructed a hyaluronic acid (HA)-functionalized platform featuring dual enzyme/ROS-triggered release and CD44-mediated active targeting (HA@Cel/NPs) for treating ulcerative colitis (UC), colitis-associated colorectal cancer (CAC), and colon cancer. HA@Cel/NPs were fabricated using β-cyclodextrin and 4-(hydroxymethyl) phenylboronic acid as dual-responsive linkers. Physicochemical properties, drug release profiles, cellular uptake, anti-inflammatory activity, macrophage polarization, and anticancer activity were systematically evaluated in vitro. In vivo biodistribution and therapeutic efficacy were assessed in UC, CAC, and colon cancer mouse models, with anti-PD-L1 combination therapy in the colon cancer setting. HA@Cel/NPs exhibited uniform size (76.87 ± 2.65 nm, PDI 0.166 ± 0.012), stayed stable for 14 days, and achieved ~71% Cel release under high H2O2/α-amylase conditions within 8 h. The nanocarriers enhanced cellular uptake and promoted M1-to-M2 macrophage polarization in inflamed macrophages, while inducing potent CT26 cell apoptosis. Orally administered HA@Cel/NPs alleviated UC severity and suppressed CAC progression, with significantly reduced tumor burden. In colon cancer, intravenous HA@Cel/NPs combined with intraperitoneal anti-PD-L1 significantly boosted CD8⁺ and CD4⁺ T cell infiltration and effectively eradicated established tumors compared with HA@Cel/NPs monotherapy. HA@Cel/NPs offer a versatile, dual-route platform that bridges inflammation management and cancer immunotherapy, distinguishing itself from single-mechanism or single-disease nanocarriers.

ID: 42610136
Title: Hyaluronic acid-coated niosomal sorafenib targets CD44 and suppresses NFκB signalling in oral squamous cell carcinoma.
Abstract: Oral squamous cell carcinoma (OSCC) remains highly lethal and is driven, in part, by chronic NF-κB-mediated inflammation. Sorafenib, a multikinase inhibitor of RAF/VEGFR/PDGFR, can suppress these pathways, but its clinical utility is limited by hydrophobicity, toxicity, and poor tumor penetration. We engineered hyaluronic acid-coated niosomes encapsulating sorafenib (SOR@Nio/HA) to enable CD44-targeted delivery to OSCC cells. SOR@Nio/HA displayed a mean hydrodynamic diameter of 177±8 nm (PDI=0.23-0.26) and high encapsulation efficiency (86.34%), with pH-responsive release (45% at pH=5.5 and 30% at pH=7.4, in 24 hr). In CAL27 cells, SOR@Nio/HA significantly enhanced cytotoxicity versus free sorafenib, lowering IC50 from 11.8±1.1 µM to 5.2±0.9 µM (P<0.01), and increased Annexin V/PI-defined apoptosis relative to controls. qRT-PCR showed suppression of NF-κB targets, with COX-2 and MMP-9 reduced to 0.35-fold and 0.32-fold of the control, respectively, alongside a pro-apoptotic shift in the BAX/BCL-2 axis. Collectively, these data indicate that SOR@Nio/HA improves intracellular delivery and potentiates sorafenib's antitumor activity by CD44-mediated uptake and inhibition of NF-κB-driven inflammatory and invasive programs. HA-guided niosomal sorafenib warrants in vivo validation as a selective nanotherapeutic strategy for OSCC.