Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

Biomimetic gold nanocages incorporating copper-human serum albumin for tumor immunotherapy via cuproptosis-lactate regulation.

Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8+) and helper T cells (CD4+). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.

A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.

Gold Nanocage-Based Photothermal Ablation Facilitates In Situ Vaccination for Melanoma Therapy.

Cancer immunotherapy represents a medical breakthrough, but there are still many patients unable to benefit from it because of the low response rate. The immunosuppressive tumor microenvironment (TME) is the main barrier to immunotherapy. Alleviating intratumoral immunosuppression is critical for improving the immune therapeutic efficacy. This work developed an in situ vaccination strategy by using gold nanocage (AuNC)-based photothermal effect in combination with an adjuvant and PD-L1 suppressor. In specific, this therapeutic strategy included three components: AuNCs as an inducer for tumor antigen production via photothermal ablation, CpG oligodeoxynucleotides as an adjuvant to amplify immune responses, and JQ1 as a PD-L1 suppressor to inhibit an immune checkpoint. The results showed that the in situ vaccination efficiently activated dendritic cells and primed T cells and exhibited a high therapeutic efficacy in the melanoma-bearing mice. This therapeutic strategy can increase the infiltration of cytotoxic T lymphocytes, suppress the PD-L1 expression in the tumor, and repolarize tumor-associated macrophages from pro-tumor M2 to the anti-tumor M1 phenotype, thereby remodeling the TME via regulating the innate immune and adaptive immune responses.

Stimuli-Responsive Gold Nanocages for Cancer Diagnosis and Treatment.

With advances in nanotechnology, various new drug delivery systems (DDSs) have emerged and played a key role in the diagnosis and treatment of cancers. Over the last two decades, gold nanocages (AuNCs) have been attracting considerable attention because of their outstanding properties. This review summarizes current advancements in endogenous, exogenous, and dual/multi-stimuli responsive AuNCs in drug delivery. This review focuses on the properties, clinical translation potential, and limitations of stimuli-responsive AuNCs for cancer diagnosis and treatment.

Preparation of NIR-Responsive Gold Nanocages as Efficient Carrier for Controlling Release of EGCG in Anticancer Application.

Hepatocellular carcinoma (HCC) is a type of cancer that has a restricted therapy option. Epigallocatechin gallate (EGCG) is one of the main biologically active ingredients in tea. A large number of studies have shown that EGCG has preventive and therapeutic effects on various tumors. In addition, the development of near-infrared (NIR)-responsive nano-platforms has been attracting cancer treatment. In this work, we designed and synthesized a strategy of gold nanocages (AuNCs) as an efficient carrier for controlling release of EGCG for anti-tumor to achieve the synergistic functions of NIR-response and inhibited tumor cell proliferation. The diameter of AuNCs is about 50 nm and has a hollow porous (8 nm) structure. Thermal imaging-graphic studies proved that the AuNCs-EGCG obtained have photothermal response to laser irradiation under near-infrared light and still maintain light stability after multiple cycles of laser irradiation. The resulted AuNCs-EGCG reduced the proliferation rate of HepG2 cells to 50% at 48 h. Western blot analysis showed that NIR-responsive AuNCs-EGCG can promote the expression of HepG2 cell apoptosis-related proteins HSP70, Cytochrome C, Caspase-9, Caspase-3, and Bax, while the expression of Bcl-2 is inhibited. Cell confocal microscopy analysis proved that AuNCs-EGCG irradiated by NIR significantly upregulates Caspase-3 by nearly 2-fold and downregulates Bcl-2 by nearly 0.33-fold, which is beneficial to promote HepG2 cell apoptosis. This study provides useful information for the NIR-responsive AuNCs-EGCG as a new type of nanomedicine for HCC.

Lactoferrin- and Dendrimer-Bearing Gold Nanocages for Stimulus-Free DNA Delivery to Prostate Cancer Cells.

Background: The use of gene therapy to treat prostate cancer is hampered by the lack of effective nanocarriers that can selectively deliver therapeutic genes to cancer cells. To overcome this, we hypothesize that conjugating lactoferrin, a tumor-targeting ligand, and the diaminobutyric polypropylenimine dendrimer into gold nanocages, followed by complexation with a plasmid DNA, would enhance gene expression and anti-proliferation activity in prostate cancer cells without the use of external stimuli. Methods: Novel gold nanocages bearing lactoferrin and conjugated to diaminobutyric polypropylenimine dendrimer (AuNCs-DAB-Lf) were synthesized and characterized. Following complexation with a plasmid DNA, their gene expression, cellular uptake and anti-proliferative efficacies were evaluated on PC-3 prostate cancer cells. Results: AuNCs-DAB-Lf was able to complex DNA at conjugate: DNA weight ratios 5:1 onwards. Gene expression was at its highest after treatment with AuNCs-DAB-Lf at a weight ratio of 10:1, as a result of a significant increase in DNA uptake mediated by the conjugate at that ratio in PC-3 cells. Consequently, the anti-proliferative activity of AuNCs-DAB-Lf-DNA encoding TNFα was significantly improved by up to 9-fold compared with DAB dendriplex encoding TNFα. Conclusion: Lactoferrin-bearing dendrimer-conjugated gold nanocages are highly promising gene delivery systems for the treatment of prostate cancer.

Platelet Membranes Coated Gold Nanocages for Tumor Targeted Drug Delivery and Amplificated Low-Dose Radiotherapy.

Continuous high doses of radiation can cause irreversible side effects and radiation resistance; thus, advanced radiosensitizers are urgently needed. To overcome this problem, we developed a nano platelet radiosensitization system (PCA) by coating the chemotherapeutic drug cisplatin (CDDP) loaded gold nanocages (AuNs) within the platelet membrane. The developed PCA system may enable AuNs to have immune escape and targeting capabilities. After administration, PCA will actively target tumor cells and avoid being cleared by the immune system. Subsequently, CDDP, which destroys tumor cell DNA, can not only kill tumor cells directly but also combine with AuNs, which deposit radiation energy into tumor tissues, reducing RT resistance. In vivo and in vitro studies revealed that the combination of PCA with RT (2Gy) efficiently inhibits tumor proliferation without causing side effects such as inflammation. To conclude, this is the first attempt to use platelet membranes to correctly transport AuNs while also accomplishing low-dose RT, which could help AuNs-based tumor RT become more effective.

Ultra-sensitive and high efficiency detection of multiple non-small cell lung cancer-related miRNAs on a single test line in catalytic hairpin assembly-based SERS-LFA strip.

Accurate quantification of multiple miRNAs biomarkers in body fluid is still a challenge for early screening of cancer. Herein, by catalytic hairpin assembly as a signal amplification strategy, we designed a novel surface-enhanced Raman scattering (SERS)-lateral flow assay (LFA) strip for ultrasensitive detection of miR-21 and miR-196a-5p in non-small cell lung cancer (NSCLC) urine on a single test (T) line. 4-mercaptobenzoic acid or 5,5'-dithiobis-2-nitrobenzoic acid as Raman molecules was labeled and two hairpin DNA sequence was modified gold nanocages (GNCs) were designed as two SERS tags. Through target miRNA-triggered catalytic hairpin assembly (CHA), the double-stranded DNAs (H1-H2 complex) formed by SERS tags and the related hairpin-structured DNA sequence 2 (H2) were immobilized on a single T line of SERS-LFA strip. This generated abundant "hot spots" because of the formation of numerous H1-H2 complex thus facilitated the SERS measurement. Through this method, two kinds of miRNAs were analyzed, resulting in limits of detection of 2.08 pM and 3.31 pM for miR-21 in PBS buffer and human urine, 1.77 pM and 2.18 pM for miR-196a-5p in PBS buffer and human urine. Significantly, the SERS-LFA strip exhibited high specificity and good repeatability toward miRNAs. The whole detection time was only 30 min, which means that the high detection efficiency of the strip. The clinical feasibility of the proposed method was also evaluated by detecting the levels of miR-21 and miR-196a-5p in urine samples from NSCLC patients and healthy subjects. The developed SERS-LFA strip has wide application prospect in biomedical research, drug development and early clinical diagnosis.

Ansamitocin P3-Loaded Gold-NanoCage Conjugated with Immune Checkpoint Inhibitor to Enhance Photo-Chemo-Thermal Maturation of Dendritic Cells for Hepatocellular Carcinoma.

Immunotherapy is a newly developed method for cancer treatment, but still generates limited response in partial patients for hepatocellular carcinoma (HCC) because the immunity cycle is limited by the tumor microenvironment (TME). Herein, we introduce multifunctional gold nanocages (AuNCs)-based nanocarriers with Ansamitocin P3 (AP3) loaded and anti-PDL1 binding (AP3-AuNCs-anti-PDL1) which can combine photothermal therapy, chemotherapeutic agent-triggered DCs maturation, and checkpoint immunotherapy in one platform. The AP3-AuNCs-anti-PDL1 using Avidin-biotin to bind anti-PDL1 on the surface of AP3-AuNCs showed specifically cellular targeting compared to AuNCs, which can increase the immune responses. The AP3-AuNCs+NIR-10 min exhibited the highly activated DCs maturation with two-fold higher than control+NIR, which can be attributed to the significant release of AP3. The results illustrated the synergistic effect of tumor-associated antigens (TAAs) and controlled AP3 release under near infrared (NIR) in triggering effective DCs maturation. Among them, AP3 release played the more important role than the TAAs under PTT in promoting T-cell activation. These results illustrate the promising potential of AuNCs-based nanocarriers combined with AP3 and the checkpoint inhibitors to strengthen the positive loop of immunity cycle.

Lactoferrin-Bearing Gold Nanocages for Gene Delivery in Prostate Cancer Cells in vitro.

BACKGROUND: Gold nanocages have been widely used as multifunctional platforms for drug and gene delivery, as well as photothermal agents for cancer therapy. However, their potential as gene delivery systems for cancer treatment has been reported in combination with chemotherapeutics and photothermal therapy, but not in isolation so far. The purpose of this work was to investigate whether the conjugation of gold nanocages with the cancer targeting ligand lactoferrin, polyethylene glycol and polyethylenimine could lead to enhanced transfection efficiency on prostate cancer cells in vitro, without assistance of external stimulation. METHODS: Novel lactoferrin-bearing gold nanocages conjugated to polyethylenimine and polyethylene glycol have been synthesized and characterized. Their transfection efficacy and cytotoxicity were assessed on PC-3 prostate cancer cell line following complexation with a plasmid DNA. RESULTS: Lactoferrin-bearing gold nanocages, alone or conjugated with polyethylenimine and polyethylene glycol, were able to condense DNA at conjugate:DNA weight ratios 5:1 and higher. Among all gold conjugates, the highest gene expression was obtained following treatment with gold complex conjugated with polyethylenimine and lactoferrin, at weight ratio 40:1, which was 1.71-fold higher than with polyethylenimine. This might be due to the increased DNA cellular uptake observed with this conjugate, by up to 8.65-fold in comparison with naked DNA. CONCLUSION: Lactoferrin-bearing gold nanocages conjugates are highly promising gene delivery systems to prostate cancer cells.

The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment.

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed.

Radiolabeling of Gold Nanocages for Potential Applications in Tracking, Diagnosis, and Image-Guided Therapy.

Gold nanocages (AuNCs) have emerged as a novel class of multifunctional nanomaterials with an array of applications in nanomedicine, including drug delivery, controlled release, as well as disease diagnosis and treatment. Labeling AuNCs with radionuclides not only offers additional therapeutic capabilities but also makes it easy to analyze their biodistribution, monitor their uptake by the tissue or organ of interest, and optimize their performance in both diagnosis and treatment. Here, an introduction to the chemical synthesis and optical properties of AuNCs is provided in the beginning. The methods developed for their radiolabeling are then showcased, followed by the use of radiolabeled AuNCs in tracking and quantifying their pharmacokinetics, including biodistribution, tumor uptake, and intratumoral distribution. Finally, their potential applications in targeted imaging and image-guided therapy are discussed.

Cancer Cell-Erythrocyte Hybrid Membrane Coated Gold Nanocages for Near Infrared Light-Activated Photothermal/Radio/Chemotherapy of Breast Cancer.

BACKGROUND: The combination of radiotherapy (RT) and chemotherapy, as a standard treatment for breast cancer in the clinic, is unsatisfactory due to chemoradioresistance and severe side effects. METHODS AND RESULTS: To address these issues, a cancer cell-erythrocyte hybrid membrane-coated doxorubicin (DOX)-loaded gold nanocage (CM-EM-GNCs@DOX) was constructed for near-infrared light (NIR)-activated photothermal/radio/chemotherapy of breast cancer. CM-EM-GNCs@DOX inherited an excellent homologous target ability from the cancer cell membrane and an immune evasion capability from the erythrocyte membrane, together resulting in highly efficient accumulation in the tumor site with decreased clearance. Following the highly efficient uptake of CM-EM-GNCs@DOX in cancer cells, the RT efficacy was remarkably amplified due to the radiosensitization effect of CM-EM-GNCs@DOX, which reduced the needed radiotherapeutic dose. Importantly, with NIR irradiation, CM-EM-GNCs@DOX exerted a high photothermal effect, which not only ruptured CM-EM-GNCs@DOX to release DOX for precise and controllable chemotherapy, but also potentiated chemo/radiotherapy by photothermal therapy. CONCLUSION: Therefore, a highly efficient and safe combined photothermal/radio/chemotherapy approach was achieved in vitro and in vivo by CM-EM-GNCs@DOX, which provided a promising strategy for treating breast cancer.

Smart gold nanocages for mild heat-triggered drug release and breaking chemoresistance.

Chemotherapy is an important modality available for cancer treatment. However, the present chemotherapy is still far from being satisfactory mainly owing to the severe side effects of the chemotherapeutic agents and drug resistance of cancer cells. Thus, reversing drug resistance by constructing an ideal chemotherapeutic strategy with the least side effects and the best efficacy is greatly needed. Here, we designed a smart nanosystem of thermo-sensitive liposome coated gold nanocages with doxorubicin (DOX) loading (LAD) for near-infrared (NIR)-triggered drug release and chemo-photothermal combination therapy. The biocompatible liposomes coating facilitated the cellular uptake of LAD and meanwhile avoided drug leakage during the circulation. More importantly, LAD exhibited controllable photothermal conversion property and produced mild heat under NIR irradiation, which not only triggered DOX release and transferred DOX from lysosome to nucleus, but also elicited the mild heat cell killing effect to improve the curative efficiency. Further mechanism study revealed that mild heat could reverse drug resistance by down-regulation of the chemoresistance-related markers (e.g., HSF-1, p53, P-gp), and inhibited DOX export and increased drug sensitiveness, thereby prominently increased the anticancer efficiency. This versatile nanoplatform with enhanced curative efficacy and lower side effect is promising to apply in the field of drug controlled release and combination tumor therapy.

Direct Visualization and Semi-Quantitative Analysis of Payload Loading in the Case of Gold Nanocages.

Upon incubation with Au nanocages, pyrrole (Py) molecules can enter the cavities by diffusing through the porous walls and then be polymerized to generate a polypyrrole (PPy) coating on the inner surface. The thicknesses of the PPy coating can serve as a direct indicator for the amount of Py molecules that diffuse into the cavity. Py molecules are able to diffuse into the cavities throughout the polymerization process, while a prolonged incubation time increases the amount of Py accumulated on both inner and outer surfaces of the nanocages. Furthermore, it is demonstrated that the dimensions of the cavity and the size of the pores in the wall are not critical parameters in determining the loading efficiency, as they do not affect the thickness of the PPy coating on the inner surface. These findings offer direct evidence to support the applications of Au nanocages as carriers for drug delivery and controlled release.

Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application.

Erythrocytes (red blood cells, RBCs) are the most abundant circulating cells in the blood and have been widely used in drug delivery systems (DDS) because of their features of biocompatibility, biodegradability, and long circulating half-life. Accordingly, a "camouflage" comprised of erythrocyte membranes renders nanoparticles as a platform that combines the advantages of native erythrocyte membranes with those of nanomaterials. Following injection into the blood of animal models, the coated nanoparticles imitate RBCs and interact with the surroundings to achieve long-term circulation. In this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to various aspects, with particular focus placed on the coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed, providing a foundation to stimulate extensive research into multifunctional nano-biomimetic systems.

A Gold Nanocage/Cluster Hybrid Structure for Whole-Body Multispectral Optoacoustic Tomography Imaging, EGFR Inhibitor Delivery, and Photothermal Therapy.

Gold nanocages (AuNCs) and gold nanoclusters (AuClusters) are two classes of advantageous nanostructures with special optical properties, and many other attractive properties. Integrating them into one nanosystem may achieve greater and smarter performance. Herein, a hybrid gold nanostructure for fluorescent and optoacoustic tomography imaging, controlled release of drugs, and photothermal therapy (PTT) is demonstrated. For this nanodrug (EA-AB), an epidermal growth factor receptor (EGFR) inhibitor erlotinib (EB) is loaded into AuNCs, which are then capped and functionalized by biocompatible AuCluster@BSA (BSA = bovine serum albumin) conjugates via electrostatic interaction. Upon cell internalization, the lysosomal proteases and low pH cause the release of EB from EA-AB, and also induce fluorescence restoration of the AuCluster for imaging. Irradiation with near-infrared light further promotes the drug release and affords a PTT effect as well. The AuNC-based nanodrug is optoacoustically active, and its biodistribution and metabolic process have been successfully monitored by whole-body and 3D multispectral optoacoustic tomography imaging. Owing to the combined actions of PTT and EGFR pathway blockage, EA-AB exhibits marked tumor inhibition efficacy in vivo.

PEGylated hyaluronidase/NIR induced drug controlled release system for synergetic chemo-photothermal therapy of hepatocellular carcinoma.

In recent years, cancer treatment has been facing the challenge of increasing antitumor efficiency and avoiding severe adverse effects simultaneously. In this study, we designed a controlled release drug delivery system, doxorubicin (Dox)-loaded and hyaluronic acid (HA)-modified PEGylated gold nanocages (AuNCs), which was designated as PEG-HAn-AuNCs/Dox (n represented 10n HA repeating units were modified on each AuNC). In this system, AuNCs were applied as the photothermal cores, Dox was employed as the model drug, HA was applied as the tumor-microenvironment responsive switch to achieve controlled release, and poly (ethylene glycol) (PEG) was used as the stealth polymer to prolong systemic circulation time. Firstly, we evaluated the physical and chemical properties of the PEG-HAn-AuNCs/Dox with different ratios of HA to AuNC and found that PEG-HA4-AuNCs/Dox was the optimal. Secondly, PEG-HA4-AuNCs/Dox revealed the feature of controlled release, namely, the drug release was triggered by hyaluronidase (HAase) and accelerated by the acidic pH and near-infrared (NIR) irradiation. And then PEG-HA4-AuNCs/Dox could be effectively delivered to a cultured SMMC-7721 cell line in vitro and the tumor tissues of the subcutaneous mouse models of hepatocellular carcinoma (HCC) in vivo. Finally, the results demonstrated the synergetic therapy, namely the combination of chemotherapy and photothermal therapy (PTT) (defined as chemo-photothermal therapy) mediated by PEG-HA4-AuNCs/Dox, could efficiently inhibit the tumor growth both in vitro and in vivo. Therefore, the advantages of PEG-HA4-AuNCs/Dox endowed it as a great potential candidate for HCC treatment.

Near-Infrared-Triggered Release of Ca2+ Ions for Potential Application in Combination Cancer Therapy.

Calcium ion (Ca2+ ), an abundant species in the body, is a potential therapeutic ion with manageable side effects. However, the delivery of such a highly charged species represents a great challenge. Here, a nanosystem based on Au nanocages (AuNCs) and a phase-change material (PCM) for delivering calcium chloride (CaCl2 ) into cancer cells and thereby triggering cell death upon near-infrared (NIR) irradiation is demonstrated. In the absence of NIR irradiation, the nanosystem, denoted CaCl2 -PCM-AuNC, shows negligible cytotoxicity because the Ca2+ ions are fully encapsulated in a solid matrix. Upon NIR irradiation, the Ca2+ ions are swiftly released due to the melting of PCM matrix in response to photothermal heating. The sudden increase in intracellular Ca2+ causes disruption to the mitochondrial Ca2+ homeostasis and thus the loss of mitochondrial membrane potential, subsequently resulting in cell apoptosis. This nanosystem provides a new method for cancer treatment by tightly managing the intracellular concentration of a physiologically essential element.