Piezoelectric Catalysis Induces Tumor Cell Senescence to Boost Chemo-Immunotherapy.

Cellular senescence, a vulnerable state of growth arrest, has been regarded as a potential strategy to weaken the resistance of tumor cells, leading to dramatic improvements in treatment efficacy. However, a selective and efficient strategy for inducing local tumor cellular senescence has not yet been reported. Herein, piezoelectric catalysis is utilized to reduce intracellular NAD+ to NADH for local tumor cell senescence for the first time. In detail, a biocompatible nanomedicine (BTO/Rh-D@M) is constructed by wrapping the piezoelectric BaTiO3/(Cp*RhCl2)2 (BTO/Rh) and doxorubicin (DOX) in the homologous cytomembrane with tumor target. After tumors are stimulated by ultrasound, negative and positive charges are generated on the BTO/Rh by piezoelectric catalysis, which reduce the intracellular NAD+ to NADH for cellular senescence and oxidize H2O to reactive oxygen species (ROS) for mitochondrial damage. Thus, the therapeutic efficacy of tumor immunogenic cell death-induced chemo-immunotherapy is boosted by combining cellular senescence, DOX, and ROS. The results indicate that 23.9% of the piezoelectric catalysis-treated tumor cells senesced, and solid tumors in mice disappeared completely after therapy. Collectively, this study highlights a novel strategy to realize cellular senescence utilizing piezoelectric catalysis and the significance of inducing tumor cellular senescence to improve therapeutic efficacy.

Green dual-template synthesis of AgPd core-shell nanoparticles with enhanced electrocatalytic activity.

A key challenge in developing an ethanol oxidation reaction is nontoxic fabrication of highly active stable and low-cost catalysts. Here we design a green synthetic strategy of AgPd bimetallic nanosphere by a dual-template cascade method. The Pd nanoshell is firstly prepared using Vapreotide acetate as a primary template, and then the Ag nanoshell acts as a secondary template for the distribution of AgPd alloy nanoparticles. The AgPd nanoparticles have core-shell structures and various sizes, and their shell thicknesses are tuned by controlling the amount of PdCl2. The six different samples are prepared, named AgPd-1, AgPd-2, AgPd-3, AgPd-4, AgPd-5, and AgPd-6, respectively. The mass current density of AgPd-5, is higher 3.87 times that of commercial Pd/C, and exhibits the best ethanol oxidation reaction activity and long-term stability. The main reasons are that the AgPd-5 possessed excellent specific surface area due to their rough structure, and Ag can remove more CO-like species. This is the first time a Vapreotide acetate/Ag-template method has been used to synthesize a AgPd core-shell structure, which would have broad application prospects for direct ethanol fuel cells.

Natural MOF-Like Photocatalytic Nanozymes Alleviate Tumor Pressure for Enhanced Nanodrug Penetration.

In oncological nanomedicine, overcoming the dual-phase high interstitial pressure in the tumor microenvironment is pivotal for enhancing the penetration and efficacy of nanotherapeutics. The elevated tumor interstitial solid pressure (TISP) is largely attributed to the overaccumulation of collagen in the extracellular matrix, while the increased tumor interstitial fluid pressure (TIFP) stems from the accumulation of fluid due to the aberrant vascular architecture. In this context, metal-organic frameworks (MOFs) with catalytic efficiency have shown potential in degrading tumor interstitial components, thereby reducing interstitial pressure. However, the potential biotoxicity of the organic components of MOFs limits their clinical translation. To circumvent this, a MOF-like photocatalytic nanozyme, RPC@M, using naturally derived cobalt phytate (CoPA) and resveratrol (Res) is developed. This nanozyme not only facilitates the decomposition of water in the tumor interstitium under photoactivation to reduce TIFP, but also generates an abundance of reactive oxygen species through its peroxidase-like activity to exert cytotoxic effects on tumor cells. Moreover, Res contributes to the reduction of collagen deposition, thereby lowering TISP. The concurrent diminution of both TISP and TIFP by RPC@M leads to enhanced tumor penetration and potent antitumor activity, presenting an innovative approach in constructing tumor therapeutic nanozymes from natural products.

Nanomedicine-based multimodal therapies: Recent progress and perspectives in colon cancer.

Colon cancer has attracted much attention due to its annually increasing incidence. Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects. In the past decade, nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention, high accumulation at tumor sites, co-loading with different drugs, and comb-ination of various therapies. This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy, radiotherapy, phototherapy (photothermal therapy and photodynamic therapy), chemodynamic therapy, gas therapy, and immunotherapy. Additionally, the therapeutic mechanisms, limitations, improvements, and future of the above therapies are discussed.

Plasmonic enhanced enzyme activity by catalytic cascade induced mutual benefit tumor starvation/immune/photothermal therapy.

Single tumor starvation therapy can activate other signaling pathways in tumor cells and easily induce tumor cell metastasis. This research proposes an intelligent nanoparticle, which is effectively combined with plasmonic and immunotherapy to realize a new strategy of "upstream consumption and downstream blocking" of nutrients in tumor sites. The intelligent nanoparticle (Ag-G/C@M) was composed of Ag NCs loaded with glucose oxidase (GOx), catalase (CAT) and coated with the tumor cytomembrane (M). Homologous targeting of tumor cytomembrane facilitated more delivery of Ag-G/C@M to tumor sites and then the plasmonic excited from Ag-G/C@M can increase the catalytic efficiency of the enzymatic reaction. Hydrogen peroxide (H2O2) produced by Ag-G/C@M through the consumption of glucose is further catalyzed by CAT to produce oxygen (O2). This self-reinforcing cascade reaction not only consumes the nutrients of tumor cells, but also the plasmonic-induced photothermal therapy can further stimulate the immune system to produce interferon-γ (IFN-γ), blocking angiogenesis and restricting the nutrient supply of tumor cells. This strategy takes the nutrition necessary for cell survival as the entry point, through endogenous continuous consumption of intracellular nutrients and containment of exogenous supplementation, combined with plasmonic thermal effect and immunotherapy to kill tumor cells, which provides a new way of treating cancer safely and effectively.

Sequential Intra-Intercellular Delivery of Nanomedicine for Deep Drug-Resistant Solid Tumor Penetration.

Cells in the center of solid tumors have always been an abyss untouched by treatments because of their deep location and increased drug resistance. Herein, we designed a rational strategy for sequential intra-intercellular delivery of nanomedicine to deep sites of drug-resistant solid tumors. In our formulation, dopamine and hemoglobin were polymerized to form a smart nanocarrier (PDA/Hb). Subsequently, the doxorubicin and nitric oxide donor were connected on the surface of PDA/Hb to obtain D/N-PDA/Hb. Ultimately, the hyaluronic acid was combined with D/N-PDA/Hb to form D/N-PDA/Hb@HA. Concretely, acidic and neutral environments of tumor cells were treated as a switch to turn on or off the drug release of a nanodrug. Meanwhile, the generation of nitric oxide in situ was exploited to favor the lysosomal escape of nanocarriers and overcome the drug resistance of deep solid tumor cells. The results indicated that the nanodrug based on sequential intra-intercellular delivery showed exciting penetration efficiency and resistance reversal of solid tumors. Conventional nanodrug delivery was highly dependent on the enhanced permeability and retention (EPR) effect and limited by tumorous interstitial fluid pressure. Plenty of drugs stayed on the surface of solid tumors, and the infiltrated drugs were inefficient due to strict resistance. To conquer this dilemma, this work proposed a new mechanism reversing the EPR effect for drug delivery, leading to better penetration and resistance reversal of solid tumors.

Seedless synthetic branched gold nanoshells for chemo-thermal antitumor therapy.

Gold nanomaterials (GNMs) are used in photothermal therapy due to their superior optical properties and excellent biocompatibility. However, the complex preparation process involving seed-mediated growth limits further clinical applications of GNMs. Herein, a novel one-pot approach to rapidly prepare liposome-based branched gold nanoshells (BGNS) as an antitumor drug nanocarrier is reported. This efficient seedless synthesis realized tunable absorption peaks of BGNS through controlling the concentration of the Au precursor solution, obtaining high absorbance in the near-infrared (NIR) window to achieve a superior photothermal effect. Hyperthermia during NIR laser irradiation can ablate the tumor and trigger drug release to achieve combined treatment. After laser irradiation, the nanocarriers disintegrated into individual gold nanoparticles (size: about 8 nm), which can be metabolized by the kidneys. Cell experiments in vitro and experiments involving mice with tumors have confirmed that the nanodrugs have strong antitumor effects. Such a flexible method provides a universal approach for rapidly preparing liposome-based gold nanoshells, which have the potential for large-scale preparation for further clinical applications.

Sensitive measurement of tumor markers somatostatin receptors using an octreotide-directed Pt nano-flakes driven electrochemical sensor.

Tumor markers play an important role in the early diagnosis and therapeutic effect monitoring of tumors. An electrochemical biosensor was developed based on multi-branched gold nanoshells (BGSs) and octreotide (OCT) functionalized Pt nano-flakes (PtNFs) modified electrodes, which was used for detection of tumor-specific markers to evaluate tumor cells. Sandwich-type nano-hybrid materials were prepared by layer-by-layer modification. First, reduced graphene oxide (RGO) and BGSs were modified as electronic materials onto glassy carbon electrodes (GCE). This modified electrode has strong electron transfer capability and large electrode surface area. The OCT was then anchored to the surface of BGSs to sensitively detect Somatostatin receptors (SSTRs) on the surface of HeLa cells. In addition, PtNFs were synthesized using a dual-template method, and OCT template on the surface of PtNFs, as an adsorption bioprobe, was used to reduce the H2O2 and amplify the electrochemical signal of biosensor. The proposed biosensor can be applied to the quantitative broad linear range of HeLa cells covering from 10 to 1 × 106 cells mL-1 (R2 = 0.9998) and the limit of detection (LOD) was 2 cells mL-1. The experimental results also show that the sensor has good stability, biocompatibility and high selectivity, which has great potential for clinical application.

Near-Infrared Responsive Bimetallic Nanovesicles for Enhanced Synergistic Chemophotothermal Therapy.

Limited therapeutic effects and obvious side effects are two critical problems affecting tumor therapy. Herein, we designed an ingenious nanocarrier, platinum/gold bimetallic-nanoshell-coated triptolide liposomes (Pt@Au-TP-Lips), to achieve enhanced chemophotothermal therapy against cancer. Compared to conventional gold nanoflower structures, the platinum/gold bimetallic (Pt@Au) core-shells exhibited broader near-infrared (NIR) absorption due to the ultrastrong plasmonic coupling effect. With NIR light irradiation, the Pt@Au nanostructure could efficiently and sustainably convert light energy into substantial heat. The ultrahigh photothermal conversion efficiency (56.5%) of Pt@Au-TP-Lips was significantly higher than that of gold nanoflowers (35.7%). Specifically, hyperthermia could induce a phase change in the liposome membrane to accelerate the release of triptolide (TP); meanwhile, it could ablate tumor cells directly and facilitate the cellular uptake of drugs to enhance chemotherapy. More importantly, owing to the cooperation of TP and platinum, Pt@Au-TP-Lips exhibited significant tumor growth suppression with a high inhibitory rate of 90.7%, achieving superior chemophotothermal combination therapy. This work provides new insight into the development of a cooperative theranostic agent for oncotherapy.

Dual Stimuli-Responsive Peptide-Based Palladium Nano-Lychee Spheres for Synergistic Antitumor Therapy.

The application of peptide-based biomaterials in nanocarriers can effectively reduce toxicity and improve the biocompatibility. In our study, a dual stimuli-responsive peptide-based drug delivery system was designed and synthesized, which was nontoxic and achieved the chem-photothermal therapy synergistic effect. Lanreotide (Lan), a kind of somatostatin analogue, was used as internal template to prepared lychee-shaped palladium (Pd) nanoparticles (Lan-PdNPs). Glutathione (GSH) and doxorubicin (DOX) were combined on the surface of Lan-PdNPs to obtain the nanosystem of Lan-PdNPs@GSH/DOX. Based on the lychee-shaped structures, the system demonstrated higher photothermal conversion performance and photothermal stability. Under NIR laser irradiation, Lan-PdNPs@GSH/DOX could convert light energy to heat in effect and accelerate drug release. Moreover, in acidic conditions, the system also exhibited the pH-responsive drug release. Owing to the synergism, the antitumor effects of Lan-PdNPs@GSH/DOX in vitro and in vivo were superior, and the inhibition ratio was much higher than that of chemotherapy or photothermal therapy alone. The good biocompatibility and nontoxicity of the system also provide the possibility for serving as an antitumor drug candidate.

Enhancing Effects of Theanine Liposomes as Chemotherapeutic Agents for Tumor Therapy.

Chemotherapy is one of the most effective methods of treating tumors in clinical study currently, but drug side effects usually are unbearable to the patient, which also makes it difficult to continue chemotherapy. Enhanced drug efficacy and reduced drug side effects are the main strategies for tumor therapy. Herein, based on biochemical regulation, theanine liposomes were designed to adjuvant doxorubicin (DOX) therapy, which can reduce the adverse reactions and enhance the effect of DOX. Stigmasterol was applied instead of traditional cholesterol for reducing the risk of cardiovascular disease. The as-prepared theanine liposomes by two methods had optimal sizes (154.8 and 169.0 nm), which can effectively accumulate in tumor tissues. In vitro experiments demonstrated that the theanine liposomes had a good effect of sustaining drug release. Cell uptake indicated that the presence of theanine can effectively inhibit glutathione (GSH) levels in cells and increase the uptake of DOX. In tumor bearing mice experiments, the combination of the theanine liposomes and DOX showed a better tumor inhibitory effect with a smaller tumor volume (2.7 fold) compared with that of the free DOX group. Meanwhile, under the mediation of theanine, the amount of doxorubicin was greatly reduced to achieve the same therapeutic effect, and the side effects of the drug were largely inhibited. Therefore, theanine liposomes have great application potential in tumor chemotherapy.