Reactive oxygen species (ROS) hold great potential in tumor pyroptosis therapy, yet they are still limited by short species lifespan and limited diffusion distance. Inducing cells into a metastable state and then applying external energy can effectively trigger pyroptosis, but systemic sensitization still faces challenges, such as limited ROS content, rapid decay, and short treatment windows. Herein, a nanohybrid-based redox homeostasis-perturbator system was designed that synergistically induce early lysosomal escape, autophagy inhibition, and redox perturbation functions to effectively sensitize cells to address these challenges. Specifically, weakly alkaline layered double hydroxide nanosheets (LDH NSs) with pH-responsive degradation properties enabled early lysosomal escape within 4 h, releasing poly(L-dopa) nanoparticles for inducing catechol-quinone redox cycling in the cytoplasm. The intracellular ROS levels were systematically rebounded by 3-4 times in tumor cells and lasted for over 4 h. Subsequently induced lysosomal stress and Ca2+ signaling activation resulted in severe mitochondrial dysfunction, as well as a perilous metastable state. Thereby, sequential near-infrared light was applied to trigger amplified stress through a local photothermal conversion. This led to sufficiently high levels of cleaved caspase-1 and GSDMD activation (2.5-2.8-fold increment) and subsequent pyroptosis response. In addition, OH- released by LDH elevated pH to alleviate the limitation of glutathione depletion by quinones at acidic pH and inhibit protective autophagy. Largely secreted inflammatory factors (2.5-5.6-fold increment), efficient maturation of dendritic cells, and further immune stimulation were boosted for tumor inhibition as a consequence. This study offers a new paradigm and insights into the synergy of internal systematic cellular sensitization and sequential external energy treatment to achieve tumor suppression through pyroptosis.

The quartz tuning fork (QTF) is a promising instrument for biosensor applications due to its advanced properties such as high sensitivity to physical quantities, cost-effectiveness, frequency stability, and high-quality factor. Nevertheless, the fork\'s small size and difficulty in modifying the prongs\' surfaces limit its wide use in experimental research. Our study presents the development of a QTF immunosensor composed of three active layers: biocompatible natural melanin nanoparticles (MNPs), glutaraldehyde (GLU), and anti-IgG layers, for the detection of immunoglobulin G (IgG). Frequency shifts of QTFs after MNP functionalization, GLU activation, and anti-IgG immobilization were measured with an Asensis QTF F-master device. Using QTF immunosensors that had been modified under optimum conditions, the performance of QTF immunosensors for IgG detection was evaluated. Accordingly, a finite element method (FEM)-based model was produced using the COMSOL Multiphysics software program (COMSOL License No. 2102058) to simulate the effect of deposited layers on the QTF resonance frequency. The experimental results, which demonstrated shifts in frequency with each layer during QTF surface functionalization, corroborated the simulation model predictions. A modelling error of 0.05% was observed for the MNP-functionalized QTF biosensor compared to experimental findings. This study validated a simulation model that demonstrates the advantages of a simulation-based approach to optimize QTF biosensors, thereby reducing the need for extensive laboratory work.

UNASSIGNED: In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target.
UNASSIGNED: In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67±3.45 for PET and 6.63±0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups.
UNASSIGNED: We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT.

UNASSIGNED: Melanin is considered the main chromophore for laser hair removal. Due to a lack of laser-absorbing chromophores, removing non-pigmented hair with laser is quite problematic with unsatisfactory outcomes. This problem could be solved by delivering more melanin to the area around the hair follicle and enhancing that area as a target for light absorption. The insolubility of Sepia melanin as an exogenous dye, in most solvents, limits its bioavailability and thus its clinical use.
UNASSIGNED: In our study, to overcome the solubility problems and increase the bioavailability of melanin for biomedical and cosmetic applications, natural sepia melanin was loaded in different nano-delivery systems (spanlastics and transfersomes) to be delivered to the hair follicles. The different formulations of melanin were prepared and characterized. In vivo skin deposition and histopathological studies were conducted on albino mice.
UNASSIGNED: Transmission electron microscopy (TEM) showed the spherical shape of the prepared vesicles with an average particle size of 252 and 262 nm and zeta potential of -22.5 and -35 mV for melanin spanlastics and melanin transfersomes, respectively. Histopathological examination of hair follicles and pilosebaceous glands for the irradiated and non-irradiated albino mice skin was studied post the application of the prepared formulations topically and subcutaneously. Qualitative statistical analysis was conducted and melanin transfersomes and melanin spanlastics showed significant damage to pilosebaceous glands and hair follicles with a p-value of 0.031 and 0.009 respectively.
UNASSIGNED: Melanin nanovesicles as transfersomes and spanlastics could be considered a promising approach for the removal of non-pigmented hair.

Periodontitis is the leading cause of adult tooth missing. Thorny bacterial biofilm and high reactive oxygen species (ROS) levels in tissue are key elements for the periodontitis process. It is meaningful to develop an advanced therapeutic system with sequential antibacterial/ antioxidant ability to meet the overall goals of periodontitis therapy. Herein, a dual-polymer functionalized melanin-AgNPs (P/D-MNP-Ag) with biofilm penetration, hydroxyapatite binding, and sequentially treatment ability are fabricated. Polymer enriched with 2-(Dimethylamino)ethyl methacrylate (D), can be protonated in an acid environment with enhanced positive charge, promoting penetration in biofilm. The other polymer is rich in phosphate group (P) and can chelate Ca2+, promoting the polymer to adhere to the hydroxyapatite surface. Melanin has good ROS scavenging and photothermal abilities, after in situ reduction Ag, melanin-AgNPs composite has sequentially transitioned between antibacterial and antioxidative ability due to heat and acid accelerated Ag+ release. The released Ag+ and heat have synergistic antibacterial effects for bacterial killing. With Ag+ consumption, the antioxidant ability of MNP recovers to scavenge ROS in the inflammatory area. When applied in the periodontitis model, P/D-MNP-Ag has good therapeutical effects to ablate biofilm, relieve inflammation state, and reduce alveolar bone loss. P/D-MNP-Ag with sequential treatment ability provides a reference for developing advanced oral biofilm eradication systems.

Osteosarcoma conventional chemotherapeutics are known for their side effects, limited options, and induction of drug resistance. This creates the need to develop new therapeutics capable of effectively destroying cancer cells with low toxicity, improving patient survival rate and their life quality. This work reports a novel drug delivery nanoplataform made of Natural Melanin Nanoparticles (MNPs), obtained from Sepia officinalis ink, with 99% incorporation efficiency of doxorubicin (Dox) without the use of non-toxic solvents. A significant photothermal effect was shown by a 36ºC increment after 10 min of laser irradiation, surpassing reported values for synthetic melanin. A sustained drug release of ca. 23% with photothermal stimuli was observed, compared to 15% without stimuli, after 48 h. This nanoplatform is obtained as a food industry side product, which makes it a natural cost-effective biomedical material. Natural MPs were applied in an osteosarcoma cell line (SaOs-2), and internalized by the cells in less than 2 h, showing cytocompatibility up to 1000 µg/mL after 72 h of contact with cells. On the contrary, when natural MNPs loaded with Dox (Dox-MNPs) were placed in contact with the SaOs-2 cells and were simultaneously receiving NIR light it was observed a 93% reduction in cancer cells in 48 h, revealing a synergistic effect between chemotherapy and phototherapy. To our knowledge this is the first time that natural MNPs extracted from Sepia officinalis were tested on an osteosarcoma cell line as chemo-photothermal agent, showing these NPs are an effective, cost-effective, reproducible, non-toxic nanoplatform for osteosarcoma treatment using combined effects.

Diabetic nephropathy (DN) is a serious complication in patients with diabetes, whose expansion process is closely related to oxidative stress caused by hyperglycemia. Herein, we report a chitosan-targeted dagliflozin-loaded melanin nanoparticle (CSMDNPs) that can selectively accumulate in injured kidneys, reduce blood glucose, and alleviate the oxidative stress-induced damage. CSMDNPs possess good dispersion and physiological stability, responsive release at acidic pH, and strong scavenging activities for various reactive oxygen and reactive nitrogen radicals. Moreover, in vitro experiments confirm that CSMDNPs have good biocompatibility, enable targeted uptake in NRK-52E renal tubular cells, and also well alleviate high glucose-induced oxidative stress. In the STZ-induced DN model, CSMDNPs exhibit high targeting distribution and retention in the damaged kidneys of DN mice according to photoacoustic imaging. At the end of CSMDNPs treatment, DN mice show a decrease in fasting blood glucose and a return to near-normal urine and blood indices. H&E, PAS, and masson pathological staining also indicates that CSMDNPs significantly inhibit the expansion of renal interstitium, glycogen, and collagen deposition, showing excellent therapeutic effects. In addition, melanin acts as both drug carrier and antioxidant without exogenous carrier introduction, exhibiting better biosafety and translational prospects.

Current treatment for chronic infectious wounds is limited due to severe drug resistance in certain bacteria. Therefore, the development of new composite hydrogels with nonantibiotic antibacterial and pro-wound repair is important. Here, we present a photothermal antibacterial composite hydrogel fabricated with a coating of Fe2+ cross-linked carboxymethyl chitosan (FeCMCS) following the incorporation of melanin nanoparticles (MNPs) and the CyRL-QN15 peptide. Various physical and photothermal properties of the hydrogel were characterized. Cell proliferation, migration, cycle, and free-radical scavenging activity were assessed, and the antimicrobial properties of the hydrogel were probed by photothermal therapy. The effects of the hydrogel were validated in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection with full-thickness injury. This effect was further confirmed by changes in cytokines associated with inflammation, re-epithelialization, and angiogenesis on the seventh day after wound formation. The MNPs demonstrated robust photothermal conversion capabilities. The composite hydrogel (MNPs/CyRL-QN15/FeCMCS) promoted keratinocyte and fibroblast proliferation and migration while exhibiting high antibacterial efficacy, effectively killing more than 95% of Gram-positive and Gram-negative bacteria. In vivo study using an MRSA-infected full-thickness injury model demonstrated good therapeutic efficacy of the hydrogel in promoting regeneration and remodeling of chronically infected wounds by alleviating inflammatory response and accelerating re-epithelialization and collagen deposition. The MNPs/CyRL-QN15/FeCMCS hydrogel showed excellent antibacterial and prohealing effects on infected wounds, indicating potential as a promising candidate for wound healing promotion.

Endothelial-mesenchymal transition (EndoMT) of vascular endothelial cells has recently been considered as a key player in the early progression of a variety of vascular and nonvascular diseases, including atherosclerosis, cancer, and organ fibrosis. However, current strategies attempting to identify pharmacological inhibitors to block the regulatory pathways of EndoMT suffer from poor selectivity, unwanted side effects, and a heterogeneous response from endothelial cells with different origins. Furthermore, EndoMT inhibitors focus on preventing EndoMT, leaving the endothelial cells that have already undergone EndoMT unresolved. Here, we report the design of a simple but powerful nanoparticle system (i.e., N-cadherin targeted melanin nanoparticles) to convert cytokine-activated, mesenchymal-like endothelial cells back to their original endothelial phenotype. We term this process \"Reversed EndoMT\" (R-EndoMT). R-EndoMT allows the impaired endothelial barriers to recover their quiescence and intactness, with significantly reduced leukocyte and cancer cell adhesion and transmigration, which could potentially stop atheromatous plaque formation and cancer metastasis in the early stages. R-EndoMT is achieved on different endothelial cell types originating from arteries, veins, and capillaries, independent of activating cytokines. We reveal that N-cadherin targeted melanin nanoparticles reverse EndoMT by downregulating an N-cadherin dependent RhoA activation pathway. Overall, this approach offers a different prospect to treat multiple EndoMT-associated diseases by designing nanoparticles to reverse the phenotypical transition of endothelial cells.

Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is a serious kidney disease with high morbidity and mortality. However, there is no effective clinical treatment strategy. Herein, we developed a CD44 targeting nanoplatform based on HA-assembled melanin NPs covalently coupled with dexamethasone for I/R-induced AKI therapy by alleviating oxidative/inflammatory- induced damage. The constructed HA-MNP-DXM NPs had good dispersion, stability, and broad-spectrum scavenging capabilities against multiple reactive free radicals. Moreover, the NPs could be efficiently internalized and exhibited antioxidative, anti-inflammatory, and antiapoptotic effects in CoCl2-stimulated renal tubular epithelial NRK-52E cells. Furthermore, the I/R-induced AKI murine model was established to evaluate the in vivo performance of NPs. The results suggested the NPs could specifically target impaired kidneys upon intravenous administration according to NIR-II fluorescence imaging and showed high biosafety. Importantly, the NPs could improve renal function, alleviate oxidative stress and inflammatory reactions, inhibit apoptosis of tubular cells, and restore mitochondrial structure and function, exhibiting excellent therapeutic effects. Further therapeutic mechanism indicated the NPs maintained the cellular/mitochondrial redox balance by modulating the Nrf2 and HO-1 expression. Therefore, the NPs can be a promising therapeutic candidate for the treatment of I/R-induced AKI.