Erratum: Author correction to 'Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics' [Acta Pharm Sin B 12 (2022) 4458-4471].

[This corrects the article DOI: 10.1016/j.apsb.2022.11.002.].

Single-cell landscape reveals the epithelial cell-centric pro-inflammatory immune microenvironment in dry eye development.

Dry eye disease (DED) is a prevalent chronic eye disease characterized by an aberrant inflammatory response in ocular surface mucosa. The immunological alterations underlying DED remain largely unknown. In this study, we employed single-cell transcriptome sequencing of conjunctival tissue from environment-induced DED mice to investigate multicellular ecosystem and functional changes at different DED stages. Our results revealed an epithelial subtype with fibroblastic characteristics and pro-inflammatory effects emerging in the acute phase of DED. We also found that T helper (Th)1, Th17, and regulatory T cells (Treg) were the dominant clusters of differentiation (CD)4+ T-cell types involved in regulating immune responses and identified three distinct macrophage subtypes, with the CD72+CD11c+ subtype enhancing chronic inflammation. Furthermore, bulk transcriptome analysis of video display terminal-induced DED consistently suggested the presence of the pro-inflammatory epithelial subtype in human conjunctiva. Our findings have uncovered a DED-associated pro-inflammatory microenvironment in the conjunctiva, centered around epithelial cells, involving interactions with macrophages and CD4+ T cells, which deepens our understanding of ocular surface mucosal immune responses during DED progression.

Entropy-Mediated High-Entropy MXenes Nanotherapeutics: NIR-II-Enhanced Intrinsic Oxidase Mimic Activity to Combat Methicillin-Resistant Staphylococcus Aureus Infection.

Bacterial infections, such as bacterial keratitis (BK) and subcutaneous abscess, pose significant challenges to global healthcare. Innovative and new antibacterial agents and antibacterial strategies are in demand to control infections in this era of high drug resistance. Nanotechnology is gradually emerging as an economically feasible and effective anti-infection treatment. High-entropy MXenes (HE MXenes) are used to confer desirable properties with exposed active sites to high-entropy atomic layers, whose potential application in the field of biomedicine remains to be explored. Herein, monolayer HE MXenes are fabricated by implementing transition metals with high entropy and low Gibbs free energy to fill the gap in the biocatalytic performance of non-high-entropy MXenes. HE MXenes are endowed with extremely strong oxidase mimic activity (Km = 0.227 mm) and photothermal conversion efficiency (65.8%) in the second near-infrared (NIR-II) biowindow as entropy increases. Subsequently, HE MXenes realize NIR-II-enhanced intrinsic oxidase mimic activity for killing methicillin-resistant Staphylococcus aureus and rapidly removing the biofilm. Furthermore, HE MXenes can effectively treat BK and subcutaneous abscess infection induced by methicillin-resistant Staphylococcus aureus as nanotherapeutic agents with minuscule side effects. Overall, monolayer HE MXenes demonstrate promising clinical application potential in the treatment of drug-resistant bacterial infections and promote the healing of infected tissues.

An in situ protonation-activated supramolecular self-assembly for selective suppression of tumor growth.

An in situ supramolecular self-assembly in the subcellular organelles could provide a new strategy to treat diseases. Herein, we report a protonation-activated in situ supramolecular self-assembly system in the lysosomes, which could destabilize the lysosome membrane, resulting in the selective suppression of cancer cells. In this system, pyridyl-functionalized tetraphenylethylene (TPE-Py) was protonated in the lysosomes of A549 lung cancer cells to form octahedron-like structures with cucurbit[8]uril (CB[8]), which impaired the integrity of the lysosome membrane, resulting in selective suppression of cancer cells. Moreover, its anticancer efficiency was also systematically evaluated in vivo, triggering the apoptosis of tumor tissues with ignorable effects on normal organs. Overall, the protonation-activated self-assembly in the lysosomes based on the host-guest complexation would provide a method for novel anti-cancer systems.

Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics.

Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment (TIM) and promoting systemic immune responses for tumor treatments. However, gasdermin D (GSDMD), a key protein in the pyroptosis process mediated by caspase-1, is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects. To address these issues, hexahistidine (His6)-metal assembly (HmA) was employed as the drug delivery vector to load nigericin (Nig) and decitabine (DAC) affording a dual-drug delivery system (Nig + DAC)@HmA. The (Nig + DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis, easily escape from the lysosome, and are highly distributed in the tumor sites. DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and caspase-1 protein activated by Nig. Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo. Our results suggest that such an easy-to-manipulate self-assembled nano-system (Nig + DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.

In Situ Forming Hydrogel as a Tracer and Degradable Lacrimal Plug for Dry Eye Treatment.

Lacrimal plug is an effective and widely therapeutic strategy to treat dry eye. However, almost all commercialized plugs are fixed in a certain design and associated with many complications, such as spontaneous plug extrusion, epiphora, and granuloma and cannot be traced in the long-term. Herein, a simple in situ forming hydrogel is developed as a tracer and degradable lacrimal plug to achieve the best match with the irregular lacrimal passages. In this strategy, methacrylate-modified silk fibroin (SFMA) is served as a network, and a self-assembled indocyanine green fluorescence tracer nanoparticle (FTN) is embedded as an indicator to develop the hydrogel plug using visible photo-crosslinking. This SFMA/FTN hydrogel plug has excellent biocompatibility and biodegradability, which can be noninvasively monitored by near-infrared light. In vivo tests based on dry eye rabbits show that the SFMA/FTN hydrogel plug can completely block the lacrimal passages and greatly improve the various clinical indicators of dry eye. These results demonstrate that the SFMA/FTN hydrogel is suitable as an injectable and degradable lacrimal plug with a long-term tracking function. The work offers a new approach to the development of absorbable plugs for the treatment of dry eye.

Immunoregulation in Diabetic Wound Repair with a Photoenhanced Glycyrrhizic Acid Hydrogel Scaffold.

M1 macrophage accumulation and excessive inflammation are commonly encountered issues in diabetic wounds and can fail in the healing process. Hence, hydrogel dressings with immunoregulatory capacity have great promise in the clinical practice of diabetic wound healing. However, current immunoregulatory hydrogels are always needed for complex interventions and high-cost treatments, such as cytokines and cell therapies. In this study, a novel glycyrrhizic acid (GA)-based hybrid hydrogel dressing with intrinsic immunoregulatory properties is developed to promote rapid diabetic wound healing. This hybrid hydrogel consists of interpenetrating polymer networks composed of inorganic Zn2+ -induced self-assembled GA and photo-crosslinked methyl acrylated silk fibroin (SF), realizing both excellent injectability and mechanical strength. Notably, the SF/GA/Zn hybrid hydrogel can regulate macrophage responses in the inflammatory microenvironment, circumventing the use of any additives. The immunomodulatory properties of the hydrogel can be harnessed for safe and efficient therapeutics that accelerate the three phases of wound repair and serve as a promising dressing for the management of diabetic wounds.

Hesperetin Exhibits Anti-Inflammatory Effects on Chondrocytes via the AMPK Pathway to Attenuate Anterior Cruciate Ligament Transection-Induced Osteoarthritis.

This study aimed to determine whether hesperetin (HPT) has chondroprotective effects against the TNF-α-induced inflammatory response of chondrocytes and related mechanisms and clarify the impact of HPT on osteoarthritis (OA) induced by anterior cruciate ligament transection (ACLT). Under tumor necrosis factor-α (TNF-α) stimulation, rat chondrocytes were treated with or without HPT. The CCK-8 assay was used to detect viability and cytotoxicity. RT-qPCR and Western blot were used to examine the expression of aggrecan, collagen type II, and inflammatory and proliferative genes/proteins in chondrocytes. Flow cytometry was used to check the cell cycle to determine whether HPT protects chondrocytes against the inhibitory effect of TNF-α on chondrocyte proliferation. In addition, RNA sequencing was used to discover possible molecular targets and pathways and then validate these pathways with specific protein phosphorylation levels. Finally, immunofluorescence staining was used to examine the phosphorylation of the AMP-activated protein kinase (AMPK) pathway. The results showed that HPT restored the upregulation of interleukin 1ß (IL-1ß), PTGS2, and MMP-13 induced by TNF-α. In addition, HPT reversed the degradation of the extracellular matrix of chondrocytes induced by TNF-α. HPT also reversed the inhibitory effect of TNF-α on chondrocyte proliferation. RNA sequencing revealed 549 differentially expressed genes (DEGs), of which 105 were upregulated and 444 were downregulated, suggesting the potential importance of the AMPK pathway. Progressive analysis showed that HPT mediated the repair of TNF-α-induced chondrocyte damage through the AMPK signaling pathway. Thus, local treatment of HPT can improve OA induced by ACLT. These findings indicated that HPT has significant protective and anti-inflammatory effects on chondrocytes through the AMPK signaling pathway, effectively preventing cartilage degradation. Given the various beneficial effects of HPT, it can be used as a potential natural drug to treat OA.

VEGF aptamer/i-motif-based drug co-delivery system for combined chemotherapy and photodynamic therapy.

BACKGROUND: Nucleic acids used as drug delivery systems (DDS) have gained attention because of their biosafety and effortless synthesis. G-quadruplex (G4) structured aptamer such as AS1411 was frequently employed to deliver photosensitizers or chemotherapeutic agents while other aptamers were seldomly reported in this field. METHODS: Herein, a chemical anticancer drug daunomycin (DNM), and a photosensitizer 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin (TMPyP) were physically assembled with a novel DNA structure composed of an aptamer of vascular endothelial growth factor (VEGF) and a cytosine (C)-rich DNA fragment (gc-34). Spectral and molecular mimicking methods were employed to research the drug loading/releasing process. The in vitro cytotoxicity was studied by MTT, ROS, cell cycle, and cell apoptotic assays and the in vivo anticancer efficiency was evaluated by the inhibitive effect on the cancerous growth of MCF-7 tumor-bearing nude mice. RESULTS: The G4-structured VEGF aptamer delivered TMPyP successfully for the first time. The designed DDS displayed sensitive VEGF/pH controlled drug release. The co-delivery of DNM and TMPyP exhibited high ROS production, significant cell cycle arresting and evident cell apoptosis, and displayed superior cytotoxicity against tumor cells compared with individual agents in vitro. In vivo studies showed that the dual-drug loaded system can greatly inhibit tumor growth with chemotherapeutic/photodynamic synergistic effects. CONCLUSION: The co-delivery of DNM and TMPyP with aptamer/C-rich DNA successfully integrates the functions of VEGF/pH stimuli-responsive drug release and chemotherapeutic/phototherapeutic modalities into one single system, and may have great potential in cancer treatment.

Tenascin-C regulates migration of SOX10 tendon stem cells via integrin-α9 for promoting patellar tendon remodeling.

Insufficient attention has been focused on the directional migration of SOX10+ tendon stem cells (STSCs) during tendon remodeling. Here, we investigate whether tenascin-C (TNC) promotes STSC motility and migration. Based on the hypothesis that TNCs induce STSC migration, RNA-sequencing (RNA-seq) was conducted, identifying 2107 differentially expressed genes (DEGs), of which 1272 were up-regulated and 835 down-regulated following treatment with TNC versus the control. The DEGs were principally involved in cell adhesion and cell membrane signal transduction. Highly enriched-related signaling included the PI3K-Akt, focal adhesion, and ECM-receptor interaction pathways. Protein interaction analysis established that TNC was positively correlated with ITGA9 (integrin-α9). Furthermore, TNC activated the phosphorylation levels of FAK and Akt, and knockdown of ITGA9 with siRNA revealed that TNC contributes to STSC migration via the targeting of ITGA9. In addition, in vivo administration of TNC promoted tissue regeneration of injured tendons. In conclusion, TNC regulated the migration of STSCs via ITGA9, thereby promoting the regeneration of tendon injuries.

Retraction: Size-selected silver nanoparticles for MALDI-TOF mass spectrometry of amyloid-beta peptides.

Retraction of 'Size-selected silver nanoparticles for MALDI-TOF mass spectrometry of amyloid-beta peptides' by Feng Ding et al., Nanoscale, 2018, 10, 22044-22054, DOI: 10.1039/C8NR07921H.

Surface modification of electrospun fibers with mechano-growth factor for mitigating the foreign-body reaction.

The implantation of synthetic polymeric scaffolds induced foreign-body reaction (FBR) seriously influence the wound healing and impair functionality recovery. A novel short peptide, mechano-growth factor (MGF), was introduced in this study to modify an electrospun polycaprolactone (PCL) fibrous scaffold to direct the macrophage phenotype transition and mitigate the FBR. In vitro studies discovered the cell signal transduction mechanism of MGF regulates the macrophage polarization via the expression of related genes and proteins. We found that macrophages response the MGF stimuli via endocytosis, then MGF promotes the histone acetylation and upregulates the STAT6 expression to direct an anti-inflammatory phenotype transition. Subsequently, an immunoregulatory electrospun PCL fibrous scaffold was modified by silk fibroin (SF) single-component layer-by-layer assembly, and the SF was decorated with MGF via click chemistry. Macrophages seeded on scaffold to identify the function of MGF modified scaffold in directing macrophage polarization in vitro. Parallelly, rat subcutaneous implantation model and rat tendon adhesion model were performed to detect the immunomodulatory ability of the MGF-modified scaffold in vivo. The results demonstrate that MGF-modified scaffold is beneficial to the transformation of macrophages to M2 phenotype in vitro. More importantly, MGF-functionalized scaffold can inhibit the FBR at the subcutaneous tissue and prevent tissue adhesion.

Gradient Biomineralized Silk Fibroin Nanofibrous Scaffold with Osteochondral Inductivity for Integration of Tendon to Bone.

Enthesis injury repair remains a huge challenge because of the unique biomolecular composition, microstructure, and mechanics in the interfacial region. Surgical reconstruction often creates new bone-scaffold interfaces with mismatched properties, resulting in poor osseointegration. To mimic the natural interface tissue structures and properties, we fabricated a nanofibrous scaffold with gradient mineral coating based on 10 × simulated body fluid (SBF) and silk fibroin (SF). We then characterized the physicochemical properties of the scaffold and evaluated its biological functions both in vitro and in vivo. The results showed that different areas of SF nanofibrous scaffold had varying levels of mineralization with disparate mechanical properties and had different effects on bone marrow mesenchymal stem cell growth and differentiation. Furthermore, the gradient scaffolds exhibited an enhancement of integration in the tendon-to-bone interface with a higher ultimate load and more fibrocartilage-like tissue formation. These findings demonstrate that the silk-based nanofibrous scaffold with gradient mineral coating can regulate the formation of interfacial tissue and has the potential to be applied in interface tissue engineering.

Polydopamine nanoparticle-dotted food gum hydrogel with excellent antibacterial activity and rapid shape adaptability for accelerated bacteria-infected wound healing.

Most commonly used wound dressings have severe problems, such as an inability to adapt to wound shape or a lack of antibacterial capacity, affecting their ability to meet the requirements of clinical applications. Here, a nanocomposite hydrogel (XKP) is developed by introducing polydopamine nanoparticles (PDA NPs) into a food gum matrix (XK, consisting of xanthan gum and konjac glucomannan, both FDA-approved food thickening agents) for skin wound healing. In this system, the embedded PDA NPs not only interact with the food gum matrix to form a hydrogel with excellent mechanical strength, but also act as photothermal transduction agents to convert near-infrared laser radiation to heat, thereby triggering bacterial death. Moreover, the XKP hydrogel has high elasticity and tunable water content, enabling it to adapt to the shape of the wound and insulate it, providing a moist environment suitable for healing. In-vivo skin wound healing results clearly demonstrate that XKP can significantly accelerate the healing of wounds by reducing the inflammatory response and promoting vascular reconstruction. In summary, this strategy provides a simple and practical method to overcome the drawbacks of traditional wound dressings, and provides further options when choosing suitable wound healing materials for clinical applications.

Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering.

Polysaccharide hydrogels are widely used in tissue engineering because of their superior biocompatibility and low immunogenicity. However, many of these hydrogels are unrealistic for practical applications as the cost of raw materials is high, and the fabrication steps are tedious. This study focuses on the facile fabrication and optimization of agarose-polydopamine hydrogel (APG) scaffolds for skin wound healing. The first study objective was to evaluate the effects of polydopamine (PDA) on the mechanical properties, water holding capacity and cell adhesiveness of APG. We observed that APG showed decreased rigidity and increased water content with the addition of PDA. Most importantly, decreased rigidity translated into significant increase in cell adhesiveness. Next, the slow biodegradability and high biocompatibility of APG with the highest PDA content (APG3) was confirmed. In addition, APG3 promoted full-thickness skin defect healing by accelerating collagen deposition and promoting angiogenesis. Altogether, we have developed a straightforward and efficient strategy to construct functional APG scaffold for skin tissue engineering, which has translation potentials in clinical practice.

FRET-based colorimetric and ratiometric sensor for visualizing pH change and application for bioimaging in living cells, bacteria and zebrafish.

Acid-alkaline balance plays a crucial role in all biological processes. Accordingly, monitoring pH changes will help us to understand the functional status of these physiological and pathological processes. Though fluorescent probes may be a useful tool for detecting pH changes, and there are many limitations to currently available probes, such as background interference, potential cytotoxicity, and poor cell permeability, which call for a solution urgently. In this work, a rhodamine-derived colorimetric and ratiometric sensor (Rh-HN) was fabricated for monitoring pH change via the mechanism of fluorescence resonance energy transfer (FRET). Rh-HN has been shown to possess several advantages over other probes, such as high sensitivity, outstanding permeability, and low toxicity. Besides, the fluorescence intensity ratio (F526/F592) of Rh-HN displays a pH-sensitive response from 2.0 to 7.5 (pKa = 5.05) and linear response from pH 3.8 to 6.4, which was desirable for mapping pH change in the biological systems. Besides, the results indicated that Rh-HN generated a pH-dependent response regulated by switchable forms between closed and opened spirolactam ring. Overall, Rh-HN has accomplished sensing and mapping of pH in living cells, bacteria, and zebrafish. Those results demonstrated that the great potential of Rh-HN in sensing and visualizing pH in the living biosystem.

Multifunctional magnetic iron oxide nanoparticles: an advanced platform for cancer theranostics.

Multifunctional magnetic nanoparticles and derivative nanocomposites have aroused great concern for multimode imaging and cancer synergistic therapies in recent years. Among the rest, functional magnetic iron oxide nanoparticles (Fe3O4 NPs) have shown great potential as an advanced platform because of their inherent magnetic resonance imaging (MRI), biocatalytic activity (nanozyme), magnetic hyperthermia treatment (MHT), photo-responsive therapy and drug delivery for chemotherapy and gene therapy. Magnetic Fe3O4 NPs can be synthesized through several methods and easily surface modified with biocompatible materials or active targeting moieties. The MRI capacity could be appropriately modulated to induce response between T1 and T2 modes by controlling the size distribution of Fe3O4 NPs. Besides, small-size nanoparticles are also desired due to the enhanced permeation and retention (EPR) effect, thus the imaging and therapeutic efficiency of Fe3O4 NP-based platforms can be further improved. Here, we firstly retrospect the typical synthesis and surface modification methods of magnetic Fe3O4 NPs. Then, the latest biomedical application including responsive MRI, multimodal imaging, nanozyme, MHT, photo-responsive therapy and drug delivery, the mechanism of corresponding treatments and cooperation therapeutics of multifunctional Fe3O4 NPs are also be explained. Finally, we also outline a brief discussion and perspective on the possibility of further clinical translations of these multifunctional nanomaterials. This review would provide a comprehensive reference for readers to understand the multifunctional Fe3O4 NPs in cancer diagnosis and treatment.

Execution of aggregation-induced emission as nano-sensors for hypochlorite detection and application for bioimaging in living cells and zebrafish.

Hypochlorite (ClO-) could be used as a diagnostic marker for inflammation and related diseases. Although there have been many reports on probes for ClO- imaging, there was still a lack of specificity and anti-interference ability. Herein, carbazole (NEC) and tetraphenylethylene (TPE) equipped with thiobarbituric acid (TBA), NEC-TBA and TPE-TBA, were synthesized and used as a fluorescence biosensor for monitoring ClO- with aggregation-induced emission (AIE) effect. we identified that TPE-TBA, with formed nanoparticles in the mean grain size at 76 nm (5 µM), was a superior probe to target ClO- over other analytes with fluorescence "turn off" strategy. Subsequently, to explore the bioimaging application, TPE-TBA was able to sense exogenous ClO- in living HeLa cells through fluorescence imaging. In zebrafish model, TPE-TBA effectively captured exogenous ClO- in the entire organization of zebrafish. Overall, these AIE-based probes merit further development as organism targeting ClO- sensors.

Synthesis and pharmacological evaluation of naftopidil-based arylpiperazine derivatives containing the bromophenol moiety.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy in men and in the absence of any effective treatments available. METHODS: For the development of potential anticancer agents, 24 kinds of naftopidil-based arylpiperazine derivatives containing the bromophenol moiety were synthesized and characterized by using spectroscopic methods. Their pharmacological activities were evaluated against human PCa cell lines (PC-3 and LNCaP) and a1-adrenergic receptors (a1-ARs; α1a, α1b, and α1d-ARs). The structure-activity relationship of these designed arylpiperazine derivatives was rationally explored and discussed. RESULTS: Among these derivatives, 3c, 3d, 3h, 3k, 3o, and 3s exhibited the most potent activity against the tested cancer cells, and some derivatives with potent anticancer activities exhibited better a1-AR subtype selectivity than others did (selectivity ratio > 10). CONCLUSION: This work provided a potential lead compound for the further development of anticancer agents for PCa therapy.

Biocompatible Hydrogels Based on Food Gums with Tunable Physicochemical Properties as Scaffolds for Cell Culture.

Hydrogels composed of food gums have gained attention for future biomedical applications, such as targeted delivery and tissue engineering. For their translation to clinical utilization, reliable biocompatibility, sufficient mechanical performance, and tunable structure of polysaccharide hydrogels are required aspects. In this work, we report a unique hybrid polysaccharide hydrogel composed of salecan and curdlan, in which the former is a thickening agent and the latter serves as a network matrix. The physicochemical properties, such as mechanical strength, thermal stability, swelling, and morphology, of the developed composite hydrogel can be accurately modulated by varying the polysaccharide content. Importantly, cytotoxicity assays show the non-toxicity of this hybrid hydrogel. Furthermore, this hydrogel system can support cell proliferation, migration, and function. Altogether, our work proposes a new strategy to build a polysaccharide-constructed hydrogel scaffold, which holds much promise for tissue engineering in terms of cell engraftment, survival, proliferation, and function.