Biomaterials with cancer cell-specific cytotoxicity: challenges and perspectives.

Significant advances have been made in materials for biomedical applications, including tissue engineering, bioimaging, cancer treatment, etc. In the past few decades, nanostructure-mediated therapeutic strategies have been developed to improve drug delivery, targeted therapy, and diagnosis, maximizing therapeutic effectiveness while reducing systemic toxicity and side effects by exploiting the complicated interactions between the materials and the cell and tissue microenvironments. This review briefly introduces the differences between the cells and tissues of tumour or normal cells. We summarize recent advances in tumour microenvironment-mediated therapeutic strategies using nanostructured materials. We then comprehensively discuss strategies for fabricating nanostructures with cancer cell-specific cytotoxicity by precisely controlling their composition, particle size, shape, structure, surface functionalization, and external energy stimulation. Finally, we present perspectives on the challenges and future opportunities of nanotechnology-based toxicity strategies in tumour therapy.

A multifunctional composite hydrogel as an intrinsic and extrinsic coregulator for enhanced therapeutic efficacy for psoriasis.

BACKGROUND: Psoriasis is a chronic relapsing immunological skin disease characterized by multiple cross-talk inflammatory circuits which are relevantly associated with abnormal cross-reactivity between immune cells and keratinocytes (KCs). It may be inadequate to eradicate complicated pathogenesis only via single-mode therapy. To provide optimal combinatory therapeutics, a nanocomposite-based hydrogel was constructed by loading methotrexate (MTX) into ZnO/Ag to realize combined multiple target therapy of psoriasis. RESULTS: In this composite hydrogel, ZnO hybrid mesoporous microspheres were utilized both as drug carriers and reactive oxygen species (ROS)-scavenging nanoparticles. A proper amount of Ag nanoparticle-anchored ZnO nanoparticles (ZnO/Ag) was functionalized with inherent immunoregulatory property. The experiments showed that ZnO/Ag nanoparticles could exhibit a self-therapeutic effect that was attributed to reducing innate cytokine profiles by inactivating p65 in proinflammatory macrophages and abrogating secretion of adaptive cytokines in KCs by downregulating ROS-mediated STAT3-cyclin D1 signaling. A preferable antipsoriatic efficacy was achieved via topical administration of this hydrogel on the imiquimod (IMQ)-induced psoriasis mice model, demonstrating the superior transdermal delivery and combined enhancement of therapeutic efficacy caused by intrinsic nanoparticles and extrinsic MTX. CONCLUSION: This composite hydrogel could serve as a multifunctional, nonirritating, noninvasive and effective transcutaneous nanoagent against psoriasis.

Highly Active Zinc Sulfide Composite Microspheres: A Versatile Template for Synthesis of a Family of Hollow Nanostructures of Sulfides.

Hollow nanostructures of metal sulfides have gained tremendous attention in catalysis, biomedicine, and energy storage and conversion owing to their intriguing structural features and fascinating physicochemical properties. Here, we reported a hard template-engaged cation exchange method to fabricate a family of binary or ternary metal sulfide (CuS, Ag2S, Bi2S3, CuxBi1-xS, ZnxCo1-xS, ZnxCd1-xS, ZnxNi1-xS, and ZnxMn1-xS) hollow microspheres via adjusting the reaction kinetic parameters including solvent and temperature in the presence of unique ZnS composite microspheres. Particularly, the shell layer thickness of metal sulfide hollow microspheres could be modulated by manipulating the reaction temperature during the cation exchanging procedure. Meanwhile, the desired elementary composition of ternary metal sulfide hollow microspheres could be achieved by varying the mole ratio and species of the metal source. This synthetic strategy could be extended to rationally design and construct other metal sulfide hollow nanostructures and provide a deep insight into the nucleation and growth process of the metal sulfide hollow microspheres with well-controlled composition and microstructures.

Engineering Hyaluronic Acid Microneedles Loaded with Mn2+ and Temozolomide for Topical Precision Therapy of Melanoma.

Topical therapy has received worldwide attention for in situ tumors owing to its higher efficacy of drug delivery. Herein, this work reports a dissolvable multifunctional hyaluronic acid microneedles (HMNs) patch coloaded with temozolomide (TMZ) and MnCl2 (TMZ/MnCl2@HMN) for chemoimmunotherapy of melanoma. HMNs can ensure the stability of TMZ over time, and exhibit fewer side effects with a localized release way. In particular, TMZ not only promotes dendritic cell maturation by triggering immunogenic cell death in tumor cells, but also induces DNA damage that can further enhance the Mn2+-activated cGAS-STING (stimulator of interferon genes pathway). As a result, the TMZ/MnCl2@HMN multifunctional platform significantly inhibits lung metastases for melanoma, providing a practical strategy for precision therapy of melanoma.

APTES-mediated Cu2(OH)3(NO3) nanomaterials on the surface of silicone catheters for abscess.

Metal-based nanomaterials have remarkable bactericidal effects; however, their toxicity cannot be disregarded. To address this concern, we developed a simple synthesis route for antibacterial catheters using metal-based nanomaterials to reduce toxicity while harnessing their excellent bactericidal properties. The grafting agent (3-aminopropyl)triethoxysilane (APTES) forms -NH2 groups on the catheter surface, onto which copper ions form a nanomaterial complex known as Cu2(OH)3(NO3) (defined as SA-Cu). The synthesized SA-Cu exhibited outstanding contact antibacterial effects, as observed through scanning electron microscopy (SEM), which revealed cell membrane crumbing and bacterial rupture on the catheter surface. Furthermore, SA-Cu exhibited excellent biosafety characteristics, as evidenced by the cell counting kit-8 (CCK-8) assay, which showed no significant cytotoxicity. SA-Cu demonstrated sustained antimicrobial capacity, with in vivo experiments demonstrating over 99% bactericidal efficacy against methicillin-resistant Staphylococcus aureus (MRSA) for two weeks. The transcriptome sequencing results suggested that SA-Cu may exert its bactericidal effects by interfering with histidine and purine metabolism in MRSA. This study presents a straightforward method for synthesizing antimicrobial silicone catheters containing copper nanomaterials using copper ions.

Cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles for targeted photodynamic and chemodynamic therapy of pancreatic cancer.

Oxidative stress induced by reactive oxygen species (ROS) is promising treatment approach for pancreatic ductal adenocarcinoma (PDAC), which is typically insensitive to conventional chemotherapy. In this study, BxPC-3 pancreatic cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles (abbreviated as BUC@ZMS) were developed for tumor-targeted cancer therapy via synergistically oxidative stress and overcoming glutathione (GSH) overexpression. Using a combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT), the BUC@ZMS core-shell nanoparticles were able to elicit the death of pancreatic cancer cells through the high production of ROS. Additionally, the BUC@ZMS core-shell nanoparticles could deplete intracellular GSH and increase the sensitivity of tumor cells to oxidative stress. The in vivo results indicated that BUC@ZMS nanoparticles can accumulate specifically in tumor locations and suppress PDAC without generating obvious toxicity. Thus, it was determined that the as-prepared core-shell nanoparticles would be a viable treatment option for solid malignancies.

Recent advances on nanomaterials for antibacterial treatment of oral diseases.

An imbalance of bacteria in oral environment can lead to a variety of oral diseases, such as periodontal disease, dental caries, and peri-implant inflammation. In the long term, in view of the increasing bacterial resistance, finding suitable alternatives to traditional antibacterial methods is an important research today. With the development of nanotechnology, antibacterial agents based on nanomaterials have attracted much attention in dental field due to their low cost, stable structures, excellent antibacterial properties and broad antibacterial spectrum. Multifunctional nanomaterials can break through the limitations of single therapy and have the functions of remineralization and osteogenesis on the basis of antibacterial, which has made significant progress in the long-term prevention and treatment of oral diseases. In this review, we have summarized the applications of metal and their oxides, organic and composite nanomaterials in oral field in recent five years. These nanomaterials can not only inactivate oral bacteria, but also achieve more efficient treatment and prevention of oral diseases by improving the properties of the materials themselves, enhancing the precision of targeted delivery of drugs and imparting richer functions. Finally, future challenges and untapped potential are elaborated to demonstrate the future prospects of antibacterial nanomaterials in oral field.

Multifunctional Hyaluronic Acid Microneedle Patch Embedded by Cerium/Zinc-Based Composites for Accelerating Diabetes Wound Healing.

Chronic nonhealing diabetic wounds are becoming increasingly severe, with high rates of mortality and disability, owing to the difficulty in wound healing caused by hyperglycemia, blocked angiogenesis, biofilm infection, and excessive oxidative stress. A multicomponent enzyme-responsive natural polymer, a hyaluronic acid (HA) microneedle, embedded in a cerium/zinc-based nanomaterial (ZCO) for the treatment of diabetic wounds is reported. ZCO-HA can destroy the oxidation balance of bacteria, kill bacteria, and scavenge reactive oxygen species (ROS) to alleviate oxidative stress via the adjustable release of Zn2+ and Ce3+ /4+ . Additionally, ZCO-HA exhibits good anti-inflammatory activity through the nuclear factor kappa-B (NF-κB) pathway, which reduces the inflammatory state of macrophages and promotes cell proliferation, migration, and angiogenesis. In vitro experiments shows that ZCO-HA accompanies mouse fibroblast migration, promoting human umbilical vein endothelial cell tube formation. In vivo studies in mice with streptozotocin-induced (STZ)-induced diabetes reveal that this microneedle accelerates wound healing without systemic toxicity. RNA transcriptome sequencing illustrates that the multicomponent HA microneedle accelerates wound healing in diabetes through cell migration and inhibits inflammatory reactions and oxidative damage in mice via the NF-κB signaling pathway.

Immunogenic Cell Death Augmented by Manganese Zinc Sulfide Nanoparticles for Metastatic Melanoma Immunotherapy.

Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immune-mediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PPIR780-ZMS), which precisely controlled the release of ZMS after being triggered by near-infrared light (NIR). Mn2+-mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PPIR780-ZMS smart bomblets in vivo. It was demonstrated that PPIR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8+) and helper T cells (CD4+) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn2+-mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.

Au nanocluster-modulated macrophage polarization and synoviocyte apoptosis for enhanced rheumatoid arthritis treatment.

The persistent progression of synovial inflammation and cartilage destruction contributes to the crosstalk between pro-inflammatory macrophages and activated fibroblast-like synoviocytes (FLSs) in a synovial microenvironment. In this work, structurally well-defined Au25 nanoclusters were synthesized to induce phenotypic polarization of pro-inflammatory macrophages and apoptosis of activated FLSs for enhanced rheumatoid arthritis treatment. These ultra-small nanoclusters significantly modulated phenotypic polarization of a pro-inflammatory M1 phenotype to an anti-inflammatory phenotype M2 for relieving inflammation. Additionally, Au25 nanoclusters can efficiently activate reactive oxygen species (ROS)-mediated apoptotic signaling pathways by inactivating thioredoxin reductase (TrxR), resulting in imbalance of the cellular redox homeostasis and initiation of FLS apoptosis. In an adjuvant-induced arthritis rat model, Au25 nanoclusters efficiently ameliorated the hyperplasia of the synovium and reduced inflammatory cell infiltration with negligible side effects. This study provided a new insight into Au nanoclusters for treating rheumatoid arthritis.

Upconversion nanoparticles@AgBiS2 core-shell nanoparticles with cancer-cell-specific cytotoxicity for combined photothermal and photodynamic therapy of cancers.

UCNPs@AgBiS2 core-shell nanoparticles that AgBiS2 coated on the surface of upconversion nanoparticles (UCNPs) was successfully prepared through an ion exchange reaction. The photothermal conversion efficiency of AgBiS2 can be improved from 14.7% to 45% due to the cross relaxation between Nd ions and AgBiS2. The doping concentration of Nd ions played a critical role in the production of reactive oxygen species (ROS) and enhanced the photothermal conversion efficiency. The NaYF4:Yb/Er/Nd@NaYF4:Nd nanoparticles endows strong upconversion emissions when the doped concentration of Nd ions is 1% in the inner core, which excites the AgBiS2 shell to produce ROS for photodynamic therapy (PDT) of cancer cells. As a result, the as-prepared NaYF4:Yb/Er/Nd@NaYF4:Nd@AgBiS2 core-shell nanoparticles showed combined photothermal/photodynamic therapy (PTT/PDT) against malignant tumors. This work provides an alternative near-infrared light-active multimodal nanostructures for applications such as fighting against cancers.

Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.

In this work, a fluoroquinolone antibiotic drug (sparfloxacin (SP)) was selected as a chemotherapy drug and photosensitizer for combined therapy. A facile chemical process was developed to incorporate SP and upconversion nanoparticles (UCNPs) into the thermally sensitive amphiphilic polymer polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane). In vitro and in vivo experiments showed that 60% of the SP molecules can be released from the micelles of thermal-sensitive polymers using a 1 W cm-2 980 nm laser, and this successfully inhibits cell migration and metastasis by inhibiting type II topoisomerases in nuclei. Additionally, intracellular metal ions were chelated by SP to induce cancer cell apoptosis by decreasing the activity of superoxide dismutase and catalase. In particular, the fluoroquinolone molecules produced singlet oxygen (1O2) to kill cancer cells, and this was triggered by UCNPs when irradiation was performed with a 980 nm laser. Overall, SP retained a weak chemotherapeutic effect, achieved enhanced photosensitizer-like effects, and was able to repurpose old drugs to elevate the therapeutic efficacy against cancer, increase the specificity for suppressing tumor migration and proliferation, and enhance apoptosis.

Facile Synthesis of Thermo-Sensitive Composite Hydrogel with Well Dispersed Ag Nanoparticles for Application in Superior Antibacterial Infections.

In this study, we have described a facile process for fabrication of multifunctional composite hydrogel, in which sodium alginate was subjected to cross-linking using Ca2+ derived from ZnO/CaCO3/Ag composite nanospheres. The ZnO/CaCO3/Ag composite nanospheres were prepared based on our previously reported AA-[Zn(OH)4]2- composite nanosphere reaction conducted with silver and calcium salt following hydrothermal method, that led to the disintegration and release of Ca2+ under acidic conditions for application as a cross-linking agentto catalyze reaction with sodium alginate. Ag nanoparticles were well-dispersed in the multifunctional composite hydrogel, exhibiting excellent antibacterial activity. Additionally, polydopamine (PDA) with photothermal effect was also added to obtain a multifunctional composite hydrogel, and this hydrogel showed photothermal conversion performance and facilitated the release of Ag+ to achieve the rapid antibacterial effect. Simultaneously, PDA NPs could scavenge free radicals and improve cell adhesion. All such features would promote wound healing. The potent antimicrobial activity of the prepared composite hydrogel was demonstrated in the mouse model of S. aureus infection, and biosafety of the hydrogel was confirmed by conducting histopathological examination in the mouse model. This type of multifunctional hydrogel wound dressing with photosensitive and antibacterial properties presents with broad applications and prospects in antibacterial treatment.

Ultrastable AgBiS2 Hollow Nanospheres with Cancer Cell-Specific Cytotoxicity for Multimodal Tumor Therapy.

Specific cytotoxicity for catalytic nanomedicine triggered by the tumor microenvironment (TME) has attracted increasing interest. In this work, we prepared AgBiS2 hollow nanospheres with narrow bandgaps via rapid precipitation in a weakly polar solvent, which lowered the intrinsic energy gap for the active production of highly reactive hydroxyl radicals (•OH), especially in the TME. The as-prepared AgBiS2 hollow nanospheres exhibited enhanced optical absorption and high photothermal conversion efficiency (44.2%). In addition, the hollow structured AgBiS2 nanospheres were found to have a peroxidase-mimicking feature to induce cancer cell-specific cytotoxicity while exhibiting negligible cytotoxicity toward normal cells, which might be attributed to the efficient production of highly reactive •OH originating from the overexpression H2O2 in the TME caused by surface catalysis. In particular, the cancer cell-specific cytotoxicity of the nanospheres was greatly enhanced both in vitro and in vivo upon irradiation with a near-infrared (NIR) laser (808 nm). The above-mentioned features of the hollow structured AgBiS2 will make it a promising candidate for tumor therapy.

Rod-based urchin-like hollow microspheres of Bi2S3: Facile synthesis, photo-controlled drug release for photoacoustic imaging and chemo-photothermal therapy of tumor ablation.

Hollow nanostructures have been evoked considerable attention owing to their intriguing hollow interior for important and potential applications in drug delivery, lithium battery, catalysis and etc. Herein, Bi2S3 hollow microspheres with rod-based urchin-like nanostructures (denoted as U-BSHM) were synthesized through a facile and rapid ion exchanging method using a particular hard template. The growth mechanism of the U-BSHM has been investigated and illustrated by the morphological evolution of the different samples at early stages. The obtained U-BSHM exhibited strong and wide UV-vis-NIR absorption ability and outstanding photothermal conversion efficiency. Thus, the U-BSHM can be used as spatio-temporal precisely controlled carrier by loading the mixture of 1-tetradecanol (phase change material, PCM) with melting point around 38 °C and hydrophilic chemotherapeutic doxorubicin hydrochloride (denoted as DOX) into the hollow interior to form (PCM + DOX)@Bi2S3 nanocomposites (denoted as PD@BS) for photoacoustic (PA) imaging and chemo-photothermal therapy of the tumors. When exposed to 808 nm near infrared light (NIR) laser irradiation, this nanocomposites could elevate the temperature of the surroundings by absorption and conversion of the NIR photons into heat energy, which inducing the triggered release of DOX from the hollow interior once the temperature reach up to the melting point of PCM. The killing efficiency of the chemo-photothermal therapy was systematically validated both in vitro and in vivo. In the meanwhile, the implanted tumor was completely restrained through PA imaging and combined therapies. Therefore, this kind of urchin-like hollow nanostructures would be used as important candidates for the multimodal bioimaging and therapy of tumors.