Boosting the sonodynamic performance of CoBiMn-layered double hydroxide nanoparticles via tumor microenvironment regulation for ultrasound imaging-guided sonodynamic therapy.

Sonodynamic therapy (SDT), a promising strategy for cancer treatment with the ability for deep tissue penetration, has received widespread attention in recent years. Sonosensitizers with intrinsic characteristics for tumor-specific curative effects, tumor microenvironment (TME) regulation and tumor diagnosis are in high demand. Herein, amorphous CoBiMn-layered double hydroxide (a-CoBiMn-LDH) nanoparticles are presented as multifunctional sonosensitizers to trigger reactive oxygen species (ROS) generation for ultrasound (US) imaging-guided SDT. Hydrothermal-synthesized CoBiMn-LDH nanoparticles are etched via a simple acid treatment to obtain a-CoBiMn-LDH nanoparticles with abundant defects. The a-CoBiMn-LDH nanoparticles give greater ROS generation upon US irradiation, reaching levels ~ 3.3 times and ~ 8.2 times those of the crystalline CoBiMn-LDH nanoparticles and commercial TiO2 sonosensitizer, respectively. This excellent US-triggered ROS generation performance can be attributed to the defect-induced narrow band gap and promoted electrons and holes (e-/h+) separation. More importantly, the presence of Mn4+ enables the a-CoBiMn-LDH nanoparticles to regulate the TME by decomposing H2O2 into O2 for hypoxia relief and US imaging, and consuming glutathione (GSH) for protection against ROS clearance. Biological mechanism analysis shows that a-CoBiMn-LDH nanoparticles modified with polyethylene glycol can serve as a multifunctional sonosensitizer to effectively kill cancer cells in vitro and eliminate tumors in vivo under US irradiation by activating p53, apoptosis, and oxidative phosphorylation-related signaling pathways.

Size-Optimized Layered Double Hydroxide Nanoparticles Promote Neural Progenitor Cells Differentiation of Embryonic Stem Cells Through the Regulation of M6A Methylation.

Purpose: The committed differentiation fate regulation has been a difficult problem in the fields of stem cell research, evidence showed that nanomaterials could promote the differentiation of stem cells into specific cell types. Layered double hydroxide (LDH) nanoparticles possess the regulation function of stem cell fate, while the underlying mechanism needs to be investigated. In this study, the process of embryonic stem cells (ESCs) differentiate to neural progenitor cells (NPCs) by magnesium aluminum LDH (MgAl-LDH) was investigated. Methods: MgAl-LDH with diameters of 30, 50, and 100 nm were synthesized and characterized, and their effects on the cytotoxicity and differentiation of NPCs were detected in vitro. Dot blot and MeRIP-qPCR were performed to detect the level of m6A RNA methylation in nanoparticles-treated cells. Results: Our work displayed that LDH nanoparticles of three different sizes were biocompatible with NPCs, and the addition of MgAl-LDH could significantly promote the process of ESCs differentiate to NPCs. 100 nm LDH has a stronger effect on promoting NPCs differentiation compared to 30 nm and 50 nm LDH. In addition, dot blot results indicated that the enhanced NPCs differentiation by MgAl-LDH was closely related to m6A RNA methylation process, and the major modification enzyme in LDH controlled NPCs differentiation may be the m6A RNA methyltransferase METTL3. The upregulated METTL3 by LDH increased the m6A level of Sox1 mRNA, enhancing its stability. Conclusion: This work reveals that MgAl-LDH nanoparticles can regulate the differentiation of ESCs into NPCs by increasing m6A RNA methylation modification of Sox1.

Synergistic Effect of Layered Double Hydroxides Nanodosage Form to Induce Apoptosis and Ferroptosis in Breast Cancer.

Background: Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. Methods: In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer. Results: The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis. Conclusion: In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

Enhancing iron content and growth of cucumber seedlings with MgFe-LDHs under low-temperature stress.

The development of cost-effective and eco-friendly fertilizers is crucial for enhancing iron (Fe) uptake in crops and can help alleviate dietary Fe deficiencies, especially in populations with limited access to meat. This study focused on the application of MgFe-layered double hydroxide nanoparticles (MgFe-LDHs) as a potential solution. We successfully synthesized and characterized MgFe-LDHs and observed that 1-10 mg/L MgFe-LDHs improved cucumber seed germination and water uptake. Notably, the application of 10 mg/L MgFe-LDHs to roots significantly increased the seedling emergence rate and growth under low-temperature stress. The application of 10 mg/L MgFe-LDHs during sowing increased the root length, lateral root number, root fresh weight, aboveground fresh weight, and hypocotyl length under low-temperature stress. A comprehensive analysis integrating plant physiology, nutrition, and transcriptomics suggested that MgFe-LDHs improve cold tolerance by upregulating SA to stimulate CsFAD3 expression, elevating GA3 levels for enhanced nitrogen metabolism and protein synthesis, and reducing levels of ABA and JA to support seedling emergence rate and growth, along with increasing the expression and activity of peroxidase genes. SEM and FTIR further confirmed the adsorption of MgFe-LDHs onto the root hairs in the mature zone of the root apex. Remarkably, MgFe-LDHs application led to a 46% increase (p < 0.05) in the Fe content within cucumber seedlings, a phenomenon not observed with comparable iron salt solutions, suggesting that the nanocrystalline nature of MgFe-LDHs enhances their absorption efficiency in plants. Additionally, MgFe-LDHs significantly increased the nitrogen (N) content of the seedlings by 12% (p < 0.05), promoting nitrogen fixation in the cucumber seedlings. These results pave the way for the development and use of LDH-based Fe fertilizers.

Highly Crystalline Copper Aluminum-Layered Double Hydroxides with Intrinsic Fenton-Like Catalytic Activity for Robust Oral Health Management.

As the main challenge of dental healthcare, oral infectious diseases are highly associated with the colonization of pathogenic microbes. However, current antibacterial treatments in the field of stomatology still lack a facile, safe, and universal approach. Herein, we report the controllable synthesis of copper aluminum-layered double hydroxides (CuAl-LDHs) with high Fenton-like catalytic activity, which can be utilized in the treatment of oral infectious diseases with negligible side effects. Our strategy can efficiently avoid the unwanted doping of other divalent metal ions in the synthesis of Cu-contained LDHs and result in the formation of binary CuAl-LDHs with high crystallinity and purity. Evidenced by experimental and theoretical results, CuAl-LDHs exhibit excellent catalytic ability toward the ·OH generation in the presence of H2O2 and hold strong affinity toward bacteria, endowing them with great catalytic sterilization against both Gram-positive and Gram-negative bacteria. As expected, these CuAl-LDHs provide outstanding treatments for mucosal infection and periodontitis by promoting wound healing and remodeling of the periodontal microenvironment. Moreover, toxicity investigation demonstrates the overall safety. Accordingly, the current study not only provides a convenient and economic strategy for treating oral infectious diseases but also extends the development of novel LDH-based Fenton or Fenton-like antibacterial reagents for further biomedical applications.

An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis.

Pyroptosis has garnered increasing attention because of its ability to trigger robust antitumor immunity. Pyroptosis is initiated by the activation of inflammasomes, which are regulated by various organelles. The collaboration among organelles offers several protective mechanisms to prevent activation of the inflammasome, thereby limiting the induction of efficient pyroptosis. Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis. In lysosomes, the negatively charged liposomes are released to recruit the NLRP3 inflammasomes through electrostatic interactions. ER stress is induced by BTZ to enhance the activation of the NLRP3 inflammasome. Meanwhile, the BLL nanocage exhibited H+-scavenging ability due to the weak alkalinity of LDH, thus disrupting the homeostasis of the lysosome and alleviating the degradation of the NLRP3 inflammasome by lysosomal-associated autophagy. Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.

Integration of CoAl-Layered Double Hydroxides on Commensal Bacteria to Enable Targeted Tumor Inhibition and Immunotherapy.

Combining targeted therapy and immunotherapy brings hope for a complete cancer cure. Due to their selective colonization and immune activation capacity, some bacteria have the potential to realize targeted immunotherapy. Herein, a biohybrid system was designed and synthesized by cladding NO3--intercalated cobalt aluminum layered double hydroxides (LDH) on anaerobic Propionibacterium acnes (PA) (PA@LDH). In this system, the covering of LDH reduces the pathogenicity of PA to normal tissues and alters its surface charge for prolonged in vivo circulation. Once the tumor site is reached, the acid-responsive degradation of LDH enables PA exposure. PA can colonize and convert nitrate ions to nitric oxide (NO) through denitrification. Then, NO reacts with intracellular O2·- to produce toxic reactive nitrogen species ONOO- and induce tumor cell apoptosis. In addition, cobalt ions released from LDH can inhibit the activity of superoxide dismutase (SOD), thus increasing the level of O2·- and further enhancing the antitumor effect. Moreover, PA exposure activates M2-to-M1 macrophage polarization and a range of immune responses, thereby achieving a sustained antitumor activity. In vitro and in vivo results reveal that the biohybrid system eliminates solid tumors and inhibits tumor metastasis effectively. Overall, the biohybrid strategy provides a new avenue for realizing simultaneous immunotherapy and targeted therapy.

Blocked Autophagy is Involved in Layered Double Hydroxide-Induced Repolarization and Immune Activation in Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME). The polar plasticity of TAMs makes them important targets for improving the immunosuppressive microenvironment of tumors. The previous study reveals that layered double hydroxides (LDHs) can effectively promote the polarization of TAMs from the anti-inflammatory M2 type to the pro-inflammatory M1 type. However, their mechanisms of action remain unexplored. This study reveals that LDHs composed of different cations exhibit distinct abilities to regulate the polarity of TAMs. Compared to Mg-Fe LDH, Mg-Al LDH has a stronger ability to promote the repolarization of TAMs from M2 to M1 and inhibit the formation of myeloid-derived suppressor cells (MDSCs). In addition, Mg-Al LDH restrains the growth of tumors in vivo and promotes the infiltration of activated immune cells into the TME more effectively. Interestingly, Mg-Al LDH influences the autophagy of TAMs; this negatively correlates with the pro-inflammatory ability of TAMs. Therefore, LDHs exert their polarization ability by inhibiting the autophagy of TAMs, and this mechanism might be related to the ionic composition of LDHs. This study lays the foundation for optimizing the performance of LDH-based immune adjuvants, which display excellent application prospects for tumor immunotherapy.

Effects of a lycopene-layered double hydroxide composite administration in cells and lungs of adult mice.

Lycopene is a natural compound with one of the highest antioxidant activities. Its consumption is associated with lower risks in lung cancer and chronic obstructive pulmonary disease, for example. Experimentally, a murine model demonstrated the ingestion of lycopene, which reduced the damage in lungs caused by cigarette smoke. Since lycopene is highly hydrophobic, its formulations in supplements and preparations for laboratory assays are based on oils, additionally, bioavailavility is low. We developed a lycopene layered double hydroxide (Lyc-LDH) composite, which is capable of transporting lycopene aqueous media. Our objective was to evaluate the cytotoxicity of Lyc-LDH and the intra-cellular production of reactive oxygen species (ROS) in J774A.1 cells. Also, in vivo assays were conducted with 50 male C57BL/6 mice intranasally treated with Lyc-LDH 10 mg/kg (LG10), Lyc-LDH 25 mg/kg (LG25) and Lyc-LDH 50 mg/kg (LG50) during five days compared against a vehicle (VG) and control (CG) group. The blood, bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed. The results revealed that Lyc-LDH composite attenuated intracellular ROS production stimulated with lipopolysacharide. In BALF, the highest doses of Lyc-LDH (LG25 and LG50) promoted influx of macrophages, lymphocytes, neutrophils and eosinophils compared to CG and VG. Also, LG50 increased the levels of IL-6 and IL-13, and promoted the redox imbalance in the pulmonary tissue. On the contrary, low concentrations did not produce significative effects. In conclusion, our results suggest that intranasal administration of high concentrations of Lyc-LDH induces inflammation as well as redox status changes in the lungs of healthy mice, however, results with low concentrations open a promising way to study LDH composites as vehicles for intranasal administration of antioxidant coadjuvants.

Sequentially activating macrophages M1 and M2 phenotypes by lipopolysaccharide-containing Mg-Fe layered double hydroxides coating on the Ti substrate.

As cells of innate immunity, macrophages are a class of innate immune cells existing in almost all tissues and play a crucial role in bone repair. However, it remains a challenge to modulate the sequential activation of the deferent phenotypes in macrophage when designing the titanium (Ti) implants. In this study, the Mg-Fe layered double hydroxides (LDHs) was coated on Ti substrate through hydrothermal treatment. Further on lipopolysaccharide (LPS) was introduced onto the LDHs through adsorption and ions exchange. The adsorption efficiency of the coating on LPS reached 72.8% in 24 h due to the anion exchange and electrostatic interactions between the LPS and the LDH layers in deionized water. The LDHs-LPS coating released a large amount of LPS in the early stage, which induced macrophages into M1 phenotype via activating TLR-4 → MyD88 and TLR-4 → Ticam-1/2 signal pathways. Subsequently, the M1 macrophages were transformed into M2 phenotype by regulating the integrin α5ß1 of cells by the nanostructures, wetting angle and Mg2+ of the coating. The LDHs-LPS coating endows Ti with the ability of stage immunomodulation, indicating the positive osteoimmunomodulatory property.

New Insights into Tolytoxin Effect in Human Cancer Cells: Apoptosis Induction and the Relevance of Hydroxyl Substitution of Its Macrolide Cycle on Compound Potency.

Scytophycins, including tolytoxin, represent a class of actin disrupting macrolides with strong antiproliferative effects on human cells. Despite intense research, little attention has been paid to scytophycin-induced cell death or the structural features affecting its potency. We show that tolytoxin and its natural analogue, 7-O-methylscytophycin B, lacking the hydroxyl substitution in its macrolactone ring, differ substantially in their cytotoxic effect. Both compounds increase the level of caspases 3/7, which are the main executioner proteases during apoptosis, in HeLa wild-type (WT) cells. However, no caspase activity was detected in HeLa cells lacking Bax/Bak proteins crucial for caspase activation via the mitochondrial pathway. Obtained data strongly suggests that scytophycins are capable of inducing mitochondria-dependent apoptosis. These findings encourage further research in structure-activity relationships in scytophycins and highlight the potential of these compounds in targeted drug delivery.

rBMSC osteogenic differentiation enhanced by graphene quantum dots loaded with immunomodulatory layered double hydroxide nanoparticles.

Bone tissue defects caused by disease, trauma, aging or genetic factors emerged as one of the main factors that endanger human health. At present, advanced development of bone tissue engineering and regenerative medicine focused on the biomaterials regulated stem cell for responsive differentiation.In vivotransplantation of allogeneic bone materials has the needs of both osteogenic and immune regulation function. In this study, we utilized the extensively proved biocompatible layered double hydroxide (LDH) nanoparticles as the nanocarrier of graphene quantum dots (GQD), the functional loading was validated by characteristics analysis of scanning electron microscopy, surface zeta potential, X-ray diffraction and fourier transform infrared spectroscopy. Further, we investigated the cellular uptake of nanoparticles in rat bone marrow derived mesenchymal stem cells, the significant enhanced endocytosis was occurred in LDH-GQD treated groups. The enhanced osteogenic differentiation abilities of LDH-GQD were systematically investigated through alkaline phosphatase staining, alizarin red staining and qPCR analysis. In addition, the anti-inflammatory regulation of LDH facilitated the phenotypic transition of macrophage in LDH-GQD nanocomposites. Overall, the successful construction and functional validation of nanomaterials in this study will provide clinical therapeutic potential in bone defects regeneration.

Biomimetic 2D layered double hydroxide nanocomposites for hyperthermia-facilitated homologous targeting cancer photo-chemotherapy.

BACKGROUND: Multi-modal therapy has attracted increasing attention as it provides enhanced effectiveness and potential stimulation of the immune community. However, low accumulation at the tumor sites and quick immune clearance of the anti-tumor agents are still insurmountable challenges. Hypothetically, cancer cell membrane (CCM) can homologously target the tumor whereas multi-modal therapy can complement the disadvantages of singular therapies. Meanwhile, moderate hyperthermia induced by photothermal therapy can boost the cellular uptake of therapeutic agents by cancer cells. RESULTS: CCM-cloaked indocyanine green (ICG)-incorporated and abraxane (PTX-BSA)-loaded layered double hydroxide (LDH) nanosheets (LIPC NSs) were fabricated for target efficient photo-chemotherapy of colorectal carcinoma (CRC). The CCM-cloaked LDH delivery system showed efficient homologous targeting and cytotoxicity, which was further enhanced under laser irradiation to synergize CRC apoptosis. On the other hand, CCM-cloaking remarkably reduced the uptake of LDH NSs by HEK 293T cells and macrophages, implying mitigation of the side effects and the immune clearance, respectively. In vivo data further exhibited that LIPC NSs enhanced the drug accumulation in tumor tissues and significantly retarded tumor progression under laser irradiation at very low therapeutic doses (1.2 and 0.6 mg/kg of ICG and PTX-BSA), without observed side effects on other organs. CONCLUSIONS: This research has demonstrated that targeting delivery efficiency and immune-escaping ability of LIPC NSs are tremendously enhanced by CCM cloaking for efficient tumor accumulation and in situ generated hyperthermia boosts the uptake of LIPC NSs by cancer cells, a potential effective way to improve the multi-modal cancer therapy.

Enhanced biocompatibility and osteogenic differentiation of mesenchymal stem cells of titanium by Sr-Ga clavate double hydroxides.

To improve in vivo osseointegration of pure titanium implant, Sr-Ga clavate double hydroxide (CDH) coating was grown in situ on a titanium (Ti) substrate with simple hydrothermal and calcination treatments at 500 °C. The obtained coating on the Ti substrate (Ti-CDH and Ti-CDH500) was researched by scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy dispersive spectroscopy (EDS). Ti-CDH exhibited a sustained release profile of metal ions and maintained a slightly alkaline environment. The CDH coating was beneficial for osteogenic differentiation of mesenchymal stem cells (MSCs), which were reflected by the results of cellular assays, including alkaline phosphatase activity (ALP), cell mineralization capability (ARS), and osteogenesis-related gene expression. Besides, Ti-CDH could effectively improve the autophagic levels in MSCs, which further promoted osteogenic differentiation of MSCs. Hence, the Ti surface with Sr-Ga CDH modification supplied a simple and effective strategy to design biomaterials for bone generation.

A novel layered double hydroxide-hesperidin nanoparticles exert antidiabetic, antioxidant and anti-inflammatory effects in rats with diabetes.

BACKGROUND: Incidence of diabetes has increased significantly worldwide over recent decades. Our objective was to prepare and characterize a novel nano-carrier of hesperidin to achieve a sustained release of hesperidin and to explore the potency of the novel formula as an antidiabetic agent compared to metformin in type 2 diabetic rats. METHODS: Hesperidin was loaded on MgAl-layered double hydroxide (LDH). The formula was characterized using Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), transmission electron microscopy, and dynamic light scattering. The release profile of hesperidin and MgAl-LDH-Hesperidin were studied in vitro. The parameters studied in vivo were blood glucose, glycated hemoglobin (HbA1c), insulin, lipid profile, and liver glycogen levels. We also investigated the levels of interleukin (IL)-17, tumor necrosis factor-Alfa (TNF-α), malondialdehyde (MDA), catalase, and the mRNA expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and nuclear factor erythroid 2-related factor-2 (NrF2). RESULTS: There were variations in the XRD patterns and FTIR confirming the physical adsorption of hesperidin on the surface of LDH. The results indicated that the diabetic rats treated with administration of antidiabetic formula, MgAl-LDH-Hesperidin, showed a beneficial effect on the levels of blood glucose, insulin, HbA1c%, and lipid profile, comparing to diabetic control rats. The antidiabetic agent also showed a significant decrease in the levels of TNF-α, IL-17, and MDA, and an increase in the level of catalase. Marked upregulation of the expression levels of mRNA for PPARγ and NrF2 were recorded. CONCLUSION: The novel nano-hesperidin formula MgAl-LDH-Hesperidin revealed a sustained release of hesperidin and exhibited antidiabetic, antihyperlipidemic, antioxidant, and anti-inflammatory properties, and also is a promising agent for effective delivery of drugs to treat type 2 diabetes.

Synergistic Cancer Photochemotherapy via Layered Double Hydroxide-Based Trimodal Nanomedicine at Very Low Therapeutic Doses.

The success of cancer therapy is always accompanied by severe side effects due to the high amount of toxic antitumor drugs that off-target normal organs/tissues. Herein, we report the development of a trifunctional layered double hydroxide (LDH) nanosystem for combined photochemotherapy of skin cancer at very low therapeutic doses. This nanosystem (ICG/Cu-LDH@BSA-DOX) is composed of acid-responsive bovine serum albumin-doxorubicin prodrug (BSA-DOX) and indocyanine green (ICG)-intercalated Cu-doped LDH nanoparticle. ICG/Cu-LDH@BSA-DOX is able to release DOX in an acid-triggered manner, efficiently and simultaneously generates heating and reactive oxygen species (ROS) upon 808 nm laser irradiation, and synergistically induces apoptosis of skin cancer cells. In vivo therapeutic evaluations demonstrate that ICG/Cu-LDH@BSA-DOX nearly eradicated the tumor tissues upon one-course treatment using very low doses of therapeutic agents (0.175 mg/kg DOX, 0.5 mg/kg Cu, and 0.25 mg/kg ICG) upon very mild 808 nm laser irradiation (0.3 W/cm2 for 2 min). This work thus provides a novel strategy to design anticancer nanomedicine for efficient combination cancer treatment with minimal side effects in clinical applications.

Defective transition metal hydroxide-based nanoagents with hypoxia relief for photothermal-enhanced photodynamic therapy.

Recently, phototherapy has attracted much attention due to its negligible invasiveness, insignificant toxicity and excellent applicability. The construction of a newly proposed nanosystem with synergistic photothermal and photodynamic tumor-eliminating properties requires a delicate structure design. In this work, a novel therapeutic nanoplatform (denoted as BCS-Ce6) based on defective cobalt hydroxide nanosheets was developed, which realized hypoxia-relieved photothermal-enhanced photodynamic therapy against cancer. Defective cobalt hydroxide exhibited high photothermal conversion efficacy at the near-infrared region (49.49% at 808 nm) as well as enhanced catalase-like activity to produce oxygen and greatly boost the singlet oxygen generation by a photosensitizer, Ce6, realizing efficacious dual-modal phototherapy. In vivo and in vitro experiments revealed that BCS-Ce6 can almost completely extinguish implanted tumors in a mouse model and present satisfactory biocompatibility during the treatment. This work sets a new angle of preparing photothermal agents and constructing comprehensive therapeutic nanosystems with the ability to modulate the hypoxic tumor microenvironment for efficient cancer therapy.

Chemodynamic/photothermal synergistic therapy based on Ce-doped Cu-Al layered double hydroxides.

The combination of chemodynamic therapy (CDT) with photothermal therapy (PTT) is an efficacious strategy in cancer treatment to acquire satisfactory therapy efficiency in the endogenous redox reaction and external laser induction. In this work, we have designed Ce doped Cu-Al layered double hydroxide (CAC-LDH) ultrathin them through a bottom-up synthesis method, and further loaded them with indocyanine green (ICG). The synthesized ICG/CAC-LDH was used as a Fenton-catalyst and photothermal agent. With the Fenton activity, the ICG/CAC-LDH nanosheets could decompose H2O2 and exhibit a low KM value (1.57 mM) and an ultra-high Vmax (4.88 × 10-6 M s-1) value. Due to the presence of oxidized metal ions, ICG/CAC-LDH could induce intracellular GSH depletion and reduce Cu2+ and Ce4+ to Cu+ and Ce3+, respectively. The generated Cu+ and Ce3+ further reacted with local H2O2 to generate toxic hydroxyl radicals (˙OH) via the Fenton reaction. Owing to the obviously enhanced absorption of ICG/CAC-LDH at 808 nm, the photothermal efficiency of ICG/CAC-LDH increased significantly compared with ICG (ΔT = 34.7 °C vs. 28.3 °C). In vitro studies substantiate the remarkable CDT/PTT efficacy, with complete apoptosis of HepG2 cancer cells (the cell viability is less than 2%) treated with 25 µg mL-1 of ICG/CAC-LDH. Furthermore, ICG/CAC-LDH could also act as a contrast agent for cancer magnetic resonance imaging (MRI) and photoacoustic imaging (PAI). These results demonstrate the potential of ICG/CAC-LDH as an integrated agent for dual-modal imaging and synergistic CDT/PTT.

Near-Infrared-Activated Lysosome Pathway Death Induced by ROS Generated from Layered Double Hydroxide-Copper Sulfide Nanocomposites.

The overdeveloped lysosomes in cancer cells are gaining increasing attention toward more precise and effective organelle-targeted cancer therapy. It is suggested that rod/plate-like nanomaterials with an appropriate size exhibited a greater quantity and longer-term lysosomal enrichment, as the shape plays a notable role in the nanomaterial transmembrane process and subcellular behaviors. Herein, a biodegradable platform based on layered double hydroxide-copper sulfide nanocomposites (LDH-CuS NCs) is successfully prepared via in situ growth of CuS nanodots on LDH nanoplates. The as-prepared LDH-CuS NCs exhibited not only high photothermal conversion and near-infrared (NIR)-induced chemodynamic and photodynamic therapeutic efficacies, but also could achieve real-time in vivo photoacoustic imaging (PAI) of the entire tumor. LDH-CuS NCs accumulated in lysosomes would then generate extensive subcellular reactive oxygen species (ROS) in situ, leading to lysosomal membrane permeabilization (LMP) pathway-associated cell death both in vitro and in vivo.

Biodegradable MnFe-hydroxide nanocapsules to enable multi-therapeutics delivery and hypoxia-modulated tumor treatment.

Developing drug delivery platforms that can modulate a tumor microenvironment and deliver multiple therapeutics to targeted tumors is critical for efficient cancer treatment. Achieving these platforms still remains a great challenge. Herein, biodegradable nanocapsules based on MnFe hydroxides (H-MnFe(OH)x) have been developed as a new type of cargo delivery with high loading capacity and catalytic activity, enabling synergetic therapy with promoted efficacy by relieving hypoxia in tumor tissues. As a proof of concept, a photosensitizer (indocyanine green, ICG) and a chemotherapeutic drug (doxorubicin, DOX) are co-loaded in nanocapsules and selectively released upon degradation of the nanocapsules in the acidic tumor microenvironment, and are promoted by near infrared irradiation. Meanwhile, Mn2+/Fe3+ ions released from the degradation of nanocapsules catalyze the conversion of H2O2 in a tumor microenvironment into oxygen, which modulates tumor hypoxia and dramatically boosts multimodal therapies. Remarkable synergistic anticancer outcomes have been demonstrated both in vitro and in vivo, paving the way towards future multifunctional therapeutic platforms.