Insights into the Roles of Natural Killer Cells in Osteoarthritis.

Osteoarthritis (OA) is now widely acknowledged as a low-grade inflammatory condition, in which the intrinsic immune system plays a significant role in its pathogenesis. While the involvement of macrophages and T cells in the development of OA has been extensively reviewed, recent research has provided mounting evidence supporting the crucial contribution of NK cells in both the initiation and advancement of OA. Accumulated evidence has emerged in recent years indicating that NK cells play a critical role in OA development and progression. This review will outline the ongoing understanding of the utility of NK cells in the etiology of OA, focusing on how NK cells interact with chondrocytes, synoviocytes, osteoclasts, and other immune cells to influence the course of OA disease.

Neutrophil to lymphocyte ratio as prognostic and predictive factor in patients with coronavirus disease 2019: A retrospective cross-sectional study.

This retrospective study was designed to explore whether neutrophil to lymphocyte ratio (NLR) is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). A cohort of patients with COVID-19 admitted to the Tongren Hospital of Wuhan University from 11 January 2020 to 3 March 2020 was retrospectively analyzed. Patients with hematologic malignancy were excluded. The NLR was calculated by dividing the neutrophil count by the lymphocyte count. NLR values were measured at the time of admission. The primary outcome was all-cause in-hospital mortality. A multivariate logistic analysis was performed. A total of 1004 patients with COVID-19 were included in this study. The mortality rate was 4.0% (40 cases). The median age of nonsurvivors (68 years) was significantly older than survivors (62 years). Male sex was more predominant in nonsurvival group (27; 67.5%) than in the survival group (466; 48.3%). NLR value of nonsurvival group (median: 49.06; interquartile range [IQR]: 25.71-69.70) was higher than that of survival group (median: 4.11; IQR: 2.44-8.12; P < .001). In multivariate logistic regression analysis, after adjusting for confounding factors, NLR more than 11.75 was significantly correlated with all-cause in-hospital mortality (odds ratio = 44.351; 95% confidence interval = 4.627-425.088). These results suggest that the NLR at hospital admission is associated with in-hospital mortality among patients with COVID-19. Therefore, the NLR appears to be a significant prognostic biomarker of outcomes in critically ill patients with COVID-19. However, further investigation is needed to validate this relationship with data collected prospectively.

Light-triggered OVA release based on CuS@poly(lactide-co-glycolide acid) nanoparticles for synergistic photothermal-immunotherapy of tumor.

The immunotherapy played a vital role in the treatment of metastatic tumor. To further enhance the effect of the immunotherapy, the combination of photothermal effect can not only eradicate the tumor cells by hyperthermia, but also improved the antigen release in vivo to achieve enhanced immune responses. In this study, a core-shell structured nanocomplex was developed by loading of ovalbumin (OVA) and copper sulfide nanoparticles (CuS-NPs) into the poly(lactide-co-glycolide acid) nanoparticles (PLGA-NPs). The CuS-NPs exhibited favorable photothermal effect, which significantly kill the 4T1 tumor cells in vitro. The photothermal effect of the CuS-NPs accelerated the OVA release, which led to higher levels of IL-6, IL-12 and TNF-α, and activation of CD8+ T cells. Both of the OVA-PLGA-NPs and CuS-NPs with NIR light irradiation contributed inhibited primary tumor while the growth of the distant tumors was not hindered. The irradiated CuS@OVA-PLGA-NPs exhibited a minimal primary tumor because of the combined effect of photothermal therapy and immunotherapy. Moreover, the irradiated CuS@OVA-PLGA-NPs showed the most extensive distribution of CD8+ T cells in the primary and distant tumor, which blocked the rise of the distant tumor. In conclusion, the CuS@OVA-PLGA-NPs presented as a promising strategy for metastatic tumor therapy.

ZJ01, a Small Molecule Inhibitor of the Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction, Reduces Hyperoxic Acute Lung Injury in a Mouse Model.

BACKGROUND Hyperoxic acute lung injury (ALI) is a complication of ventilation in patients with respiratory failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) has an important role in ALI. Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2. ZJ01 is a small molecule inhibitor of Keap1-Nrf2 protein-protein interaction (PPI) that can reduce Keap1-induced inhibition of Nrf2. This study aimed to investigate the effects of ZJ01 and the heme oxygenase-1 (HO-1) inhibitor, zinc protoporphyrin IX (ZnPP IX), in a mouse model of hyperoxic ALI. MATERIAL AND METHODS C57BL/6J mice included five study groups: the room air+vehicle-treated group; the room air+ZJ01 group; the hyperoxia+vehicle-treated group; the hyperoxia+ZJ01 group; and the hyperoxia+ZJ01+ZnPP IX group. ZJ01, ZnPP IX, or vehicle were given 1 h after the hyperoxia challenge. The lungs from the mice were harvested at 72 h following the hyperoxia challenge. RESULTS Hyperoxia exposure for 72 h increased the activity of myeloperoxidase, the lung water content, the levels of tumor necrosis factor-alpha (TNF-alpha), and matrix metalloprotease-9 (MMP-9) in the vehicle-treated mice. ZJ01 treatment reduced hyperoxia-induced inflammation and increased the activation of Nrf2 and HO-1 compared with the vehicle-treated mice. Histology of the lungs showed that ZJ01 treatment reduced the changes of hyperoxia-induced ALI. Pretreatment with ZnPP IX reversed the beneficial effect of ZJ01. CONCLUSIONS ZJ01, a Keap1-Nrf2 PPI inhibitor, reduced hyperoxic ALI in a mouse model through the Nrf2/HO-1 pathway.

Correction to: Preparation and Evaluation of Cubic Nanoparticles for Improved Transdermal Delivery of Propranolol Hydrochloride.

Xin Zhou is a co-corresponding author of this published article and the affiliation should read "Xin Zhou1, 3".

Preparation and Evaluation of Cubic Nanoparticles for Improved Transdermal Delivery of Propranolol Hydrochloride.

Transdermal drug delivery of propranolol hydrochloride (PRH) is promising for the treatment of infantile hemangioma (IH). Clinically used PRH hydrogel fails to reach the deep IH for complete recovery. In this study, the PRH-loaded cubic nanoparticles (CNPs) were prepared to promote the transdermal effect of PRH. A remote drug loading method was developed to prepare the PRH-CNPs. For the traditional passive drug loading method, the largest encapsulation efficiency (EE%) was around 50%. The remote drug loading was performed by increasing the pH of the mixture of blank CNPs and PRH solution. The optimal PRH-CNPs showed an EE% of 90.15 ± 2.44% at pH 8.5. The permeation of the PRH solution was poor while the PRH-CNPs showed greatly enhanced skin permeation. It was found that smaller-sized PRH-CNPs contributed to increased skin permeation and retention. In addition, the PRH-CNPs had higher cytotoxicity towards the EOMA cells when compared with the PRH solution. During storage for 1 month, the PRH-CNPs kept stable size distribution, pH, and EE%. In conclusion, results of this study suggested that the PRH-CNPs could be a potential candidate for the treatment of the IH by transdermal delivery.

[Progress in study of spectrum-effect relationship of traditional Chinese medicine and discussions].

Spectrum-effect relationship of traditional Chinese medicine is a scientific method based on fingerprint of traditional Chinese medicine, which studied the correlations between fingerprint and activity. The method revealed the activity related peaks and clarified the active components. It provided directions and thoughts for the clarification of pharmacodynamic material basis and establishment of evaluation method to reflect the inherent quality of traditional Chinese medicine. In this text we would make a systematic review about the progress in the study of spectrum-effect relationship of traditional Chinese medicine after summarized the latest years of investigations from researchers at home and abroad, including the establishment of fingerprint, efficacy evaluation, and data processing. The key problems in each part were clarified and corresponding discussions were made, providing thoughts and advices for the following study of spectrum-effect relationship of traditional Chinese medicine. At last we made a expecting on the development trend of spectrum-effect relationship of traditional Chinese medicine.

[Studies on pharmacokinetics features of characteristic active ingredients of daidai flavone extract in different physiological status].

In order to explore the clinical hypolipidemic features of Daidai flavone extract, the pharmacokinetics features of characteristic active ingredients of Daidai flavone extract in normal and hyperlipemia rats were studied and compared. The study established the quantitative determination method of naringin and neohesperidin in plasma by UPLC-MS. Study compared the pharmacokinetics differences of naringin and noehesperidin in normal and hyperlipemia rats on the basis of establishment of hyperlipemia model. Results indicated that the pharmacokinetics features of characteristic active ingredients of Daidai flavone extract in normal and hyperlipemia rats showed significant differences. The C(max) of naringin and neohesperidin in hyperlipemia rats plasma after oral administration of Daidai flavone extract increased obviously, while t1/2, MRT and AUC0-24 h decreased, compared to normal rats. But t(max) showed no differences to that of normal rats. The results further proved Daidai flavone extract would have better hypolipidemic effect in the hyperlipemia pathological status. And the characteristic active ingredients naringin and noehesperidin were the material base of Daidai flavone extract to express the hypolipidemic effect.

Promoting effects of ferric ions on Microcystis aeruginosa growth and arsenate accumulation and reduction at different phosphorus environments.

The effects of different dissolved organic phosphorus (DOP) associated with distinct iron conditions (iron deficient (dFe), ferric ions (Fe3+), and colloidal iron (CFe)) on algal growth and arsenate (As(V)) metabolism were systematically evaluated and compared in Microcystis aeruginosa. Two chemical forms of DOP (D-glucose-6-phosphate (GP) and phytic acid (PA)), as well as dissolved inorganic phosphorus (DIP), were employed as distinct phosphorus environments. The results revealed that As(V) metabolism of M. aeruginosa was more influenced by different phosphorus forms than by different iron conditions. Conversely, the release of microcystins in the media was found to be significantly more affected by the different phosphorus forms than by the iron conditions. Moreover, DOP was observed to promote arsenic (As) biotransformation, particularly the efflux of methylated As from a single algal cell, whereas DIP was found to primarily facilitate As(V) accumulation in algae. The total As metabolism amount per algal cell under PA was observed to be five times that observed under DIP and GP. The influence of iron conditions on the synthesis of algal metabolites was notable, as evidenced by the metabolites identified in algae of aliphatic (δ 1.28-1.68), humic acid-like and aromatic protein-like substances through 1H-NMR spectra and three-dimensional excitation-emission matrix fluorescence spectroscopy analysis. This impact was particularly notable at Fe3+ conditions, due to the role of Fe3+ as a micronutrient with highly bioavailable forms, which enhanced the synthesis of organic compounds in algae and promoted algal growth. Consequently, Fe3+ could inhibit As accumulation under DIP but promote it under DOP. The obtained results facilitate a more comprehensive understanding of the combined role of different phosphorus forms and iron conditions in algal bloom outbreaks and As(V) metabolism.

Self-delivery nanodrug to manipulate tumor microenvironment for boosting photodynamic cancer immunotherapy.

Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host's immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the "cold" properties of tumors.

The molecular binding sequence transformation of soil organic matter and biochar dissolved black carbon antagonizes the transport of 2,4,6-trichlorophenol.

Dissolved organic matter (DOM) and dissolved black carbon (DBC) are significant environmental factors that influence the transport of organic pollutants. However, the mechanisms by which their molecular diversity affects pollutant transport remain unclear. This study elucidates the molecular binding sequence and adsorption sites through which DOM/DBC compounds antagonize the transport of 2,4,6-trichlorophenol (TCP) using column experiments and modelling. DBC exhibits a high TCP adsorption rate (kn = 5.32 × 10-22 mol1-n∙Ln-1∙min-1) and conditional stability constant (logK = 5.19-5.74), indicating a strong binding affinity and antagonistic effect on TCP. This is attributed to the high relative content of lipid/protein compounds in DBC (25.65 % and 30.28 %, respectively). Moreover, the small molecule lipid compounds showed stronger TCP adsorption energy (Ead = -0.0071 eV/-0.0093 eV) in DOM/DBC, combined with two-dimensional correlation spectroscopy model found that DOM/DBC antagonized TCP transport in the environment through binding sequences that transformed from lipid/protein small molecule compounds to lignin/tannin compounds. This study used a multifaceted approach to comprehensively assess the impact of DOM/DBC on TCP transport. It reveals that the molecular diversity of DOM/DBC is a critical factor affecting pollutant transport, providing important insights into the environmental trend and ecological effects of pollutants.

Co-delivery of Paclitaxel/Atovaquone/Quercetin to regulate energy metabolism to reverse multidrug resistance in ovarian cancer by PLGA-PEG nanoparticles.

Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.

Stretchable Organohydrogel with Adhesion, Self-Healing, and Environment-Tolerance for Wearable Strain Sensors.

Stretchable hydrogels as landmark soft materials have been efficiently utilized in the field of wearable sensing devices. However, these soft hydrogels mostly cannot integrate transparency, stretchability, adhesiveness, self-healing, and environmental adaptability into one system. Herein, a fully physically cross-linked poly(hydroxyethyl acrylamide)-gelatin dual-network organohydrogel is prepared in a phytic acid-glycerol binary solvent via a rapid ultraviolet light initiation. The introduction of gelatin as the second network endows the organohydrogel with desirable mechanical performance (high stretchability up to 1240%). The presence of phytic acid not only synergizes with glycerol to impart environment-tolerance to the organohydrogel (from -20 to 60 °C) but also increases the conductivity. Moreover, the organohydrogel demonstrates a durable adhesive performance toward diverse substrates, a high self-healing efficiency through heat treatment, and favorable optical transparency (transmittance of 90%). Furthermore, the organohydrogel achieves high sensitivity (gauge factor of 2.18 at 100% strain) and rapid response time (80 ms) and could detect both tiny (a low detection limit of 0.25% strain) and large deformations. Therefore, the assembled organohydrogel-based wearable sensors are capable of monitoring human joint motions, facial expression, and voice signals. This work proposes a facile route for multifunctional organohydrogel transducers and promises the practical application of flexible wearable electronics in complex scenarios.

Tough, recyclable and biocompatible carrageenan-modified polyvinyl alcohol ionic hydrogel with physical cross-linked for multimodal sensing.

Biocompatibility hydrogel conductors are considered as sustainable bio-electronic materials for the application of wearable sensors and implantable devices. However, they mostly face the limitations of mismatched mechanical properties with skin tissue and the difficulty of recycling. In this regard, here, a biocompatible, tough, reusable sensor based on physical crosslinked polyvinyl alcohol (PVA) ionic hydrogel modified with ι-carrageenan (ι-CG) helical network was reported. Through simulating the ion transport and network structure of biological systems, the ionic hydrogels with skin-like mechanical features exhibit large tensile strain of 640 %, robust fracture strength of 800 kPa, soft modulus and high fatigue resistance. Meanwhile, the ionic hydrogel-based sensors possess a high response to strain/pressure over a wide range and could be utilized for multimodal sensing of human activity signals. Benefit from biosafety and temperature reversibility of ι-CG and PVA endow hydrogels with not only biocompatibility, but also meaningfully recyclability. The as-prepared hydrogels could be freely reconstructed into new flexible electronics and safely integrated with the human skin. It could be anticipated that the physically cross-linked ionic hydrogel conductor could expand the options for next-generation bio-based sensors.

Effect of oil-modified crosslinked starch as a new fat replacer on gel properties, water distribution, and microstructures of pork meat batter.

This work investigated the effects of oil-modified crosslinked starch (Oil-CTS) as a fat replacer on the gel properties, water distribution, microstructures, and fatty acid composition of pork meat batter. Results showed that the replacement of pork back fat by Oil-CTS could improve the gel performance in terms of rheological property, texture, and water-holding capacity (WHC), and reduce the water mobility of pork meat gels, which caused by the formation of a more ordered and denser protein network structure. Additionally, when the fat was replaced by Oil-CTS partially or totally (25-100 %), the total fat content in pork meat gels decreased by 16.5-82 % and the saturated fatty acids (SFAs) content decreased from 5.87 g/100 g in untreated sample to 1.17-4.88 g/100 g in starch-replacing-fat samples, indicating Oil-CTS could be used as a fat replacer to prepare the low-fat meat products.

Remote Loading of Hydrophilic Drug into Cubosomes by Transmembrane pH-Gradient and Characterization of Drug-Loaded Cubosomes Prepared by Different Method.

The encapsulation efficiency (EE) of hydrophobic drug into cubosomes was high by conventional methods, while poor for the hydrophilic drug. In this study, a remote loading method based on transmembrane pH-gradient was applied to prepare hydrophilic drug loaded cubosomes. Several hydrophilic drugs were selected and studied. Results showed just part of the investigated drugs were successfully loaded into cubosomes by the remote loading method, whereas all the drugs failed to be encapsulated by the high-pressure homogenization method. The EE based on remote loading method was affected by the solubility, LogP, number of rings, and polarizability of the drug independent of the number of hydrogen acceptor and hydrogen donor. And the drugs that had high EE by remote loading method were BCS class 1 or 2. In addition, the EE base on remote loading method was significantly affected by the external water pH of cubosomes and drug concentration. The size of drug-loaded cubosomes by remote loading method mainly depended on the pre-formed blank cubosomes, which was bigger than that by high-pressure homogenization method. The preparation method affected the liquid crystalline structure of acidic drug loaded cubosomes, while showed no obvious effect on that of basic drug loaded cubosomes. The release of drug was susceptible to the pH of release medium independent of the preparation method. The drug-loaded cubosomes prepared by different method all showed favorable stability during storage. The remote loading method was a promising approach for the efficient encapsulation of hydrophilic drug into cubosomes. This study laid a foundation for the application of remote loading method on the preparation of hydrophilic drug loaded cubosomes.

Integrating Fly Ash-Controlled Surface Morphology and Candle Grease Coating: Access to Highly Hydrophobic Poly (L-lactic Acid) Composite for Anti-Icing Application.

New ways of recycling fly ash are of great significance for reducing the environmental pollution. In this work, biodegradable hydrophobic poly (L-lactic acid)/fly ash composites for anti-icing application were successfully fabricated via a facile solvent-volatilization-induced phase separation approach. A silane coupling agent of 3-(Trimethoxysilyl) propyl methacrylate was used to decorate a fly ash surface (FA@KH570) for strengthening the interface bonding between fly ash and poly (L-lactic acid). Moreover, FA@KH570 could obviously enhance the crystallinity of poly (L-lactic acid) (PLLA)/FA@KH570 composites, which accelerated the conversion from the liquid-liquid to the liquid-solid phase separation principle. Correspondingly, the controllable surface morphology from smooth to petal-like microspheres was attained simply by adjusting the FA@KH570 content. After coating nontoxic candle grease, the apparent contact angle of 5 wt% PLLA/FA@KH570 composite was significantly increased to an astonishing 151.2°, which endowed the composite with excellent anti-icing property. This strategy paves the way for recycling waste fly ash and manufacturing hydrophobic poly (L-lactic acid) composite for potential application as an anti-icing material for refrigerator interior walls.

Different oil-modified cross-linked starches: In vitro digestibility and its relationship with their structural and rheological characteristics.

This study investigated the structure, rheological behaviors and in vitro digestibility of oil-modified cross-linked starches (Oil-CTS). Gelatinized Oil-CTS were hard to be digested due to its intact granule shapes and the presence of surface-oil, which acted as physical barriers that inhibited the diffusion and penetration of enzymes to starch. Besides, the less amylose content in Oil-CTS (23.19-26.96%) than other starches (26.84-29.20%) contributed to its low digestibility because amylose with less α-1,6 linkages was more easily attacked by amyloglucosidase than amylopectin. Moreover, heat treatment during oil could shorten the amylopectin chain length and destroy the ordered structures, thus increasing enzymatic hydrolysis on starch. Pearson correlation analysis indicated rheological parameters were not significantly correlated with digestion parameters (p > 0.05). Overall, despite the damage caused by heat to molecular structures, physical barrier effect caused by surface-oil layers and integrity of swollen granules was the most critical contributor to the low digestibility of Oil-CTS.

Review on typical organophosphate diesters (di-OPEs) requiring priority attention: Formation, occurrence, toxicological, and epidemiological studies.

The impact of primary metabolites of organophosphate triesters (tri-OPEs), namely, organophosphate diesters (di-OPEs), on the ecology, environment, and humans cannot be ignored. While extensive studies have been conducted on tri-OPEs, research on the environmental occurrence, toxicity, and health risks of di-OPEs is still in the preliminary stage. Understanding the current research status of di-OPEs is crucial for directing future investigations on the production, distribution, and risks associated with environmental organophosphate esters (OPEs). This paper specifically reviews the metabolization process from tri-OPEs to di-OPEs and the occurrence of di-OPEs in environmental media and organisms, proposes typical di-OPEs in different media, and classifies their toxicological and epidemiological findings. Through a comprehensive analysis, six di-OPEs were identified as typical di-OPEs that require prioritized research. These include di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) phosphate (BBOEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCIPP), and diphenyl phosphate (DPHP). This review provides new insights for subsequent toxicological studies on these typical di-OPEs, aiming to improve our understanding of their current status and provide guidance and ideas for research on the toxicity and health risks of di-OPEs. Ultimately, this review aims to enhance the risk warning system of environmental OPEs.

Cubosomes-assisted transdermal delivery of doxorubicin and indocyanine green for chemo-photothermal combination therapy of melanoma.

Melanoma is a highly aggressive form of skin cancer with limited therapeutic options. Chemo-photothermal combination therapy has demonstrated potential for effectively treating melanoma, and transdermal administration is considered the optimal route for treating skin diseases due to its ability to bypass first-pass metabolism and enhance drug concentration. However, the stratum corneum presents a formidable challenge as a significant barrier to drug penetration in transdermal drug delivery. Lipid-nanocarriers, particularly cubosomes, have been demonstrated to possess significant potential in augmenting drug permeation across the stratum corneum. Herein, cubosomes co-loaded with doxorubicin (DOX, a chemotherapeutic drug) and indocyanine green (ICG, a photothermal agent) (DOX-ICG-cubo) transdermal drug delivery system was developed to enhance the therapeutic efficiency of melanoma by improving drug permeation. The DOX-ICG-cubo showed high encapsulation efficiency of both DOX and ICG, and exhibited good stability under physiological conditions. In addition, the unique cubic structure of the DOX-ICG-cubo was confirmed through transmission electron microscopy (TEM) images, polarizing microscopy, and small angle X-ray scattering (SAXS). The DOX-ICG-cubo presented high photothermal conversion efficiency, as well as pH and thermo-responsive DOX release. Notably, the DOX-ICG-cubo exhibited enhanced drug permeation efficiency, good biocompatibility, and improved in vivo anti-melanoma efficacy through the synergistic effects of chemo-photothermal therapy. In conclusion, DOX-ICG-cubo presented a promising strategy for melanoma treatment.