Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy.

Immunogenic cell death (ICD) often results in the production and accumulation of adenosine (ADO), a byproduct that negatively impacts the therapeutic effect as well as facilitates tumor development and metastasis. Here, an innovative strategy is elaborately developed to effectively activate ICD while avoiding the generation of immunosuppressive adenosine. Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

Metabolic Regulation-Mediated Reversion of the Tumor Immunosuppressive Microenvironment for Potentiating Cooperative Metabolic Therapy and Immunotherapy.

Tumor cells exhibit heightened glucose (Glu) consumption and increased lactic acid (LA) production, resulting in the formation of an immunosuppressive tumor microenvironment (TME) that facilitates malignant proliferation and metastasis. In this study, we meticulously engineer an antitumor nanoplatform, denoted as ZLGCR, by incorporating glucose oxidase, LA oxidase, and CpG oligodeoxynucleotide into zeolitic imidazolate framework-8 that is camouflaged with a red blood cell membrane. Significantly, ZLGCR-mediated consumption of Glu and LA not only amplifies the effectiveness of metabolic therapy but also reverses the immunosuppressive TME, thereby enhancing the therapeutic outcomes of CpG-mediated antitumor immunotherapy. It is particularly important that the synergistic effect of metabolic therapy and immunotherapy is further augmented when combined with immune checkpoint blockade therapy. Consequently, this engineered antitumor nanoplatform will achieve a cooperative tumor-suppressive outcome through the modulation of metabolism and immune responses within the TME.

Immunostimulant Hydrogel-Guided Tumor Microenvironment Reprogramming to Efficiently Potentiate Macrophage-Mediated Cellular Phagocytosis for Systemic Cancer Immunotherapy.

Macrophage-mediated cellular phagocytosis (MMCP) plays a critical role in conducting antitumor immunotherapy but is usually impaired by the intrinsic phagocytosis evading ability of tumor cells and the immunosuppressive tumor microenvironment (TME). Herein, a MMCP-boosting hydrogel (TCCaGM) was elaborately engineered by encapsulating granulocyte-macrophage colony-stimulating factor (GM-CSF) and a therapeutic nanoplatform (TCCaN) that preloaded with the tunicamycin (Tuni) and catalase (CAT) with the assistance of CaCO3 nanoparticles (NPs). Strikingly, the hypoxic/acidic TME was efficiently alleviated by the engineered hydrogel, "eat me" signal calreticulin (CRT) was upregulated, while the "don't eat me" signal CD47 was downregulated on tumor cells, and the infiltrated DCs were recruited and activated, all of which contributed to boosting the macrophage-mediated phagocytosis and initiating tumor-specific CD8+ T cells responses. Meanwhile, the remodeled TME was beneficial to accelerate the polarization of tumor-associated macrophages (TAMs) to the antitumoral M1-like phenotype, further heightening tumoricidal immunity. With the combination of PD-1 antibody (αPD-1), the designed hydrogel significantly heightened systemic antitumor immune responses and long-term immunological effects to control the development of primary and distant tumors as well as suppress tumor metastasis and recurrence, which established an optimal strategy for high-performance antitumor immunotherapy.

Fused Cytomembrane-Camouflaged Nanoparticles for Tumor-Specific Immunotherapy.

Tumor immunotherapy is commonly hindered by inefficient delivery and presentation of tumor antigens as well as immunosuppressive tumor microenvironment. To overcome these barriers, a tumor-specific nanovaccine capable of delivering tumor antigens and adjuvants to antigen-presenting cells and modulating the immune microenvironment to elicit strong antitumor immunity is reported. This nanovaccine, named FCM@4RM, is designed by coating the nanocore (FCM) with a bioreconstituted cytomembrane (4RM). The 4RM, which is derived from fused cells of tumorous 4T1 cells and RAW264.7 macrophages, enables effective antigen presentation and stimulation of effector T cells. FCM is self-assembled from Fe(II), unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG), and metformin (MET). CpG, as the stimulator of toll-like receptor 9, induces the production of pro-inflammatory cytokine and the maturation of cytotoxic T lymphocytes (CTLs), thereby enhancing antitumor immunity. Meanwhile, MET functions as the programmed cell death ligand 1 inhibitor and can restore the immune responses of T cells against tumor cells. Therefore, FCM@4RM exhibits high targeting capabilities toward homologous tumors that develop from 4T1 cells. This work offers a paradigm for developing a nanovaccine that systematically regulates multiple immune-related processes to achieve optimal antitumor immunotherapy.

Specific activation of cGAS-STING pathway by nanotherapeutics-mediated ferroptosis evoked endogenous signaling for boosting systemic tumor immunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity, but specific activation of STING pathway is still an enormous challenge. Herein, a ferroptosis-induced mitochondrial DNA (mtDNA)-guided tumor immunotherapy nanoplatform (designated as HBMn-FA) was elaborately developed for activating and boosting STING-based immunotherapy. On the one hand, the high-levels of reactive oxygen species (ROS) in tumor cells induced by HBMn-FA-mediated ferroptosis elicited mitochondrial stress to cause the release of endogenous signaling mtDNA, which specifically initiate cGAS-STING pathway with the cooperation of Mn2+. On the other hand, the tumor-derived cytosolic double-stranded DNA (dsDNA) from debris of death cells caused by HBMn-FA further activated the cGAS-STING pathway in antigen-presenting cells (e.g., DCs). This bridging of ferroptosis and cGAS-STING pathway could expeditiously prime systemic antitumor immunity and enhance the therapeutic efficacy of checkpoint blockade to suppress tumor growth in both localized and metastatic tumor models. The designed nanotherapeutic platform paves the way for novel tumor immunotherapy strategies that are based on specific activation of STING pathway.

Interference of Glucose Bioavailability of Tumor by Engineered Biohybrids for Potentiating Targeting and Uptake of Antitumor Nanodrugs.

The chemotherapy efficacy of nanodrugs is restricted by poor tumor targeting and uptake. Here, an engineered biohybrid living material (designated as EcN@HPB) is constructed by integrating paclitaxel and BAY-876 bound human serum albumin nanodrugs (HPB) with Escherichia coli Nissle 1917 (EcN). Due to the inherent tumor tropism of EcN, EcN@HPB could actively target the tumor site and competitively deprive glucose through bacterial respiration. Thus, albumin would be used as an alternative nutrient source for tumor metabolism, which significantly promotes the internalization of HPB by tumor cells. Subsequently, BAY-876 internalized along with HPB nanodrugs would further depress glucose uptake of tumor cells via inhibiting glucose transporter 1 (GLUT1). Together, the decline of glucose bioavailability of tumor cells would activate and promote the macropinocytosis in an AMP-activated protein kinase (AMPK)-dependent manner, resulting in more uptake of HPB by tumor cells and boosting the therapeutic outcome of paclitaxel.

Essential thrombocythemia with non-ST-segment elevation myocardial infarction as the first manifestation: A case report.

BACKGROUND: We report a case of essential thrombocythemia (ET) in a 44-year-old male who exhibited non-ST-segment-elevation myocardial infarction (NSTEMI) as the first manifestation without known cardiovascular risk factors (CVRFs). For the first time, we reported a left main trifurcation lesion in NSTEMI caused by ET, including continuous stenosis lesions from the left main to the ostial left anterior descending (LAD) artery and an obvious thrombotic lesion in the ostial and proximal left circumflex (LCX) artery. There was 60% diffuse stenosis in the left main (LM) that extended to the ostial LAD, thrombosis of the ostial LAD and proximal LCX, and 90% stenosis in the proximal LCX. During the operation, thrombus aspiration was performed, but no obvious thrombus was aspirated. Performing the kissing balloon technique (KBT) in the LCX and LM unexpectedly increased the narrowness of the LAD. Then, the single-stent crossover technique, final kissing balloon technique and proximal optimization technique (POT) were performed. On the second day after percutaneous coronary intervention (PCI), the number of platelets (PLTs) still increased significantly to as high as 696 × 109/L. The bone marrow biopsy done later, together with JAK2 (exon 14) V617F mutation, confirms the diagnosis of ET. Hydroxyurea was administered to inhibit bone marrow proliferation to control the number of PLTs. CASE SUMMARY: A 44-year-old male patient went to a local hospital for treatment for intermittent chest pain occurring over 8 h. The examination at the local hospital revealed elevated cTnI and significantly elevated platelet. Then, he was diagnosed with acute myocardial infarction and transferred to our hospital for emergency interventional treatment by ambulance. During the operation, thrombus aspiration, the single-stent crossover technique, final kissing balloon technique and POT were performed. Dual antiplatelet therapy comprising aspirin and ticagrelor was used after PCI. Evidence of mutated JAK2 V617F and bone marrow biopsy shown the onset of ET. Together with JAK2 (exon 14) V617F mutation, ET was diagnosed according to the World Health Organization (WHO) diagnostic criteria, and the patient was placed on hydroxyurea. During the one-year postoperative period, repeated examinations showed a slight increase in PLTs, but the patient no longer had chest tightness, chest pain or bleeding or developed new thromboembolisms. CONCLUSION: Routine physical examinations and screenings are conducive to the early detection of ET, and the risk for thrombosis should be assessed. Then, active antiplatelet therapy and myelosuppression therapy should be used for high-risk ET patients.

Biomedical polymers: synthesis, properties, and applications.

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

A Self-Driven Bioreactor Based on Bacterium-Metal-Organic Framework Biohybrids for Boosting Chemotherapy via Cyclic Lactate Catabolism.

The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.

A tumor-cell biomimetic nanoplatform embedding biological enzymes for enhanced metabolic therapy.

A tumor cell membrane-camouflaged therapeutic system was fabricated to eliminate tumors by embedding apyrase and glucose oxidase (GOx) into zeolitic imidazolate framework-8 (ZIF-8) nanoparticles for tumor-targeted metabolic therapy. Experimental results demonstrated that these functional nanoparticles could disturb the energy supply of tumor cells by depleting ATP and glucose and efficiently induce tumor cell death.

Recent Advances in Engineered Materials for Immunotherapy-Involved Combination Cancer Therapy.

Immunotherapy that can activate immunity or enhance the immunogenicity of tumors has emerged as one of the most effective methods for cancer therapy. Nevertheless, single-mode immunotherapy is still confronted with several critical challenges, such as the low immune response, the low tumor infiltration, and the complex immunosuppression tumor microenvironment. Recently, the combination of immunotherapy with other therapeutic modalities has emerged as a powerful strategy to augment the therapeutic outcome in fighting against cancer. In this review, recent research advances of the combination of immunotherapy with chemotherapy, phototherapy, radiotherapy, sonodynamic therapy, metabolic therapy, and microwave thermotherapy are summarized. Critical challenges and future research direction of immunotherapy-based cancer therapeutic strategy are also discussed.

Cell primitive-based biomimetic functional materials for enhanced cancer therapy.

Cell primitive-based functional materials that combine the advantages of natural substances and nanotechnology have emerged as attractive therapeutic agents for cancer therapy. Cell primitives are characterized by distinctive biological functions, such as long-term circulation, tumor specific targeting, immune modulation etc. Moreover, synthetic nanomaterials featuring unique physical/chemical properties have been widely used as effective drug delivery vehicles or anticancer agents to treat cancer. The combination of these two kinds of materials will catalyze the generation of innovative biomaterials with multiple functions, high biocompatibility and negligible immunogenicity for precise cancer therapy. In this review, we summarize the most recent advances in the development of cell primitive-based functional materials for cancer therapy. Different cell primitives, including bacteria, phages, cells, cell membranes, and other bioactive substances are introduced with their unique bioactive functions, and strategies in combining with synthetic materials, especially nanoparticulate systems, for the construction of function-enhanced biomaterials are also summarized. Furthermore, foreseeable challenges and future perspectives are also included for the future research direction in this field.

miRNA-Specific Unlocking of Drug-Loaded Metal-Organic Framework Nanoparticles: Targeted Cytotoxicity toward Cancer Cells.

UiO-68 metal-organic framework nanoparticles (NMOFs) are loaded with a doxorubicin drug (fluorescent dye analogs) and locked by means of structurally engineered duplex nucleic acid structures, where one strand is covalently linked to the NMOFs and the second strand is hybridized with the anchor strand. Besides the complementarity of the second strand to the anchor sequence, it includes the complementary sequence to the microRNAs (miRNA)-21 or miRNA-221 that is specific miRNA biomarker for MCF-7 breast cancer cells or OVCAR-3 ovarian cancer cells. In the presence of the respective miRNA biomarkers, the miRNA-induced displacement of the strand associated with the anchor strand proceeds, resulting in the release of DNA/miRNA duplexes. The released duplexes are, however, engineered to be digested in the presence of exonuclease III, Exo III, a process that recycles the miRNAs and provides the autonomous amplified unlocking of the NMOFs and the release of the doxorubicin load (or the fluorescent dye analogs) even at low concentrations of miRNA. Preliminary cell experiments reveal that the respective NMOFs are unlocked by the miRNA-21 or miRNA-221, resulting in selective cytotoxicity toward MCF-7 breast cancer cells or OVCAR-3 ovarian cancer cells.

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials.

Recently, diverse functional materials that take subcellular structures as therapeutic targets are playing increasingly important roles in cancer therapy. Here, particular emphasis is placed on four kinds of therapies, including chemotherapy, gene therapy, photodynamic therapy (PDT), and hyperthermal therapy, which are the most widely used approaches for killing cancer cells by the specific destruction of subcellular organelles. Moreover, some non-drug-loaded nanoformulations (i.e., metal nanoparticles and molecular self-assemblies) with a fatal effect on cells by influencing the subcellular functions without the use of any drug molecules are also included. According to the basic principles and unique performances of each treatment, appropriate strategies are developed to meet task-specific applications by integrating specific materials, ligands, as well as methods. In addition, the combination of two or more therapies based on multifunctional nanostructures, which either directly target specific subcellular organelles or release organelle-targeted therapeutics, is also introduced with the intent of superadditive therapeutic effects. Finally, the related challenges of critical re-evaluation of this emerging field are presented.

Targeted VEGF-triggered release of an anti-cancer drug from aptamer-functionalized metal-organic framework nanoparticles.

Amino-triphenyl dicarboxylate-bridged Zr4+ metal-organic framework nanoparticles (NMOFs), 100-130 nm, are modified with a nucleic acid complementary to the VEGF aptamer. The nucleic acid-functionalized NMOFs were loaded with the anti-cancer drug doxorubicin (or Rhodamine 6G as a drug model), and the loaded NMOFs were capped by hybridization with the VEGF aptamer that yielded VEGF-responsive duplex nucleic acid gates. In the presence of VEGF, a biomarker over-expressed in cancer cells, selective unlocking of the gates proceeds through the formation of VEGF/aptamer complexes, resulting in the release of the loads. In addition, the VEGF aptamer locking units were conjugated to the AS1411 aptamer sequence that binds to nucleolin receptors associated with cancer cells, resulting in the construction of cancer-cell targeted VEGF-responsive doxorubicin-loaded NMOFs. The different drug-loaded stimuli-responsive NMOFs reveal selective permeation into MDA-MB-231 breast cancer cells, compared to their incorporation into normal MCF-10A breast cells, with a two-fold enhanced incorporation into the MDA-MB-231 cells of the AS1411 aptamer-functionalized NMOFs. Cytotoxicity experiments revealed impressive selective apoptosis of the doxorubicin-loaded NMOFs towards the MDA-MB-231 cancer cells compared to the normal MCF-10A breast cells. A 55% and 70% MDA-MB-231 cell apoptosis was observed upon subjecting the cells to the VEGF aptamer and the VEGF aptamer/AS1411 aptamer conjugate-caged NMOFs, respectively, for a time-interval of three days, where only <10% apoptosis of the MCF-10A cells was observed under similar conditions.

Stimuli-responsive nucleic acid-functionalized metal-organic framework nanoparticles using pH- and metal-ion-dependent DNAzymes as locks.

A versatile approach to modify metal-organic framework nanoparticles (NMOFs) with nucleic acid tethers, using the "click chemistry" method is introduced. The nucleic acid-functionalized NMOFs are used to prepare stimuli-responsive carriers of loads (fluorescence probes or anti-cancer drugs). Two different stimuli-responsive nucleic acid-based NMOFs are presented. One system involves the preparation of pH-responsive NMOFs. The NMOFs are loaded with fluorophores or doxorubicin anti-cancer drug and locked in the NMOFs by pH-responsive DNA duplex capping units. At pH = 5.0 the capping units are unlocked, leading to the release of the loads. The AS1411 aptamer is conjugated to the locking units as the targeting unit for the nucleolin biomarker present in cancer cells. The pH-responsive doxorubicin-loaded NMOFs and, in particular, the AS1411 aptamer-modified pH-responsive NMOFs reveal selective, targeted, cytotoxicity toward MDA-MB-231 breast cancer cells. A second system involves the synthesis of NMOFs that are loaded with fluorophores or doxorubicin and capped with metal-ion-dependent DNAzyme/substrate complexes as locking units (metal ion = Mg2+ or Pb2+ ions). In the presence of the respective metal ions, the nucleic acid locking units are cleaved off, resulting in the release of the loads. Also, "smart" Mg2+-ion-dependent DNAzyme capped doxorubicin-loaded NMOFs are synthesized via the integration of the ATP aptamer sequence in the loop domain of the Mg2+-dependent DNAzyme. The unlocking of these NMOFs proceeds effectively only in the presence of ATP and Mg2+ ions, acting as cooperative triggers. As ATP is over-expressed in cancer cells, the "smart" carrier provides sense-and-treat functions. The "smart" ATP/Mg2+-triggered doxorubicin-loaded NMOFs reveal selective cytotoxicity toward MDA-MB-231 cancer cells. Beyond the use of the metal-ion-dependent DNAzymes as ion-responsive locks of drug-loaded NMOF carriers, the DNAzyme-capped fluorophore-loaded NMOFs are successfully applied as functional units for multiplexed ion-sensing and for the design of logic-gate systems.

Overcoming the Heat Endurance of Tumor Cells by Interfering with the Anaerobic Glycolysis Metabolism for Improved Photothermal Therapy.

In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.

Mesoporous silica-based versatile theranostic nanoplatform constructed by layer-by-layer assembly for excellent photodynamic/chemo therapy.

Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+. The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN-Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform.

Rational design of multifunctional magnetic mesoporous silica nanoparticle for tumor-targeted magnetic resonance imaging and precise therapy.

In this paper, a multifunctional theranostic magnetic mesoporous silica nanoparticle (MMSN) with magnetic core was developed for magnetic-enhanced tumor-targeted MR imaging and precise therapy. The gatekeeper ß-cyclodextrin (ß-CD) was immobilized on the surface of mesoporous silica shell via platinum(IV) prodrug linking for reduction-triggered intracellular drug release. Then Arg-Gly-Asp (RGD) peptide ligand was further introduced onto the gatekeeper ß-CD via host-guest interaction for cancer targeting purpose. After active-targeting endocytosis by cancer cells, platinum(IV) prodrug in MMSNs would be restored to active platinum(II) drug in response to the innative reducing microenvironment in cancer cells, resulting in the detachment of ß-CD gatekeeper and thus simultaneously triggering the in situ release of anticancer drug doxorubicin (DOX) entrapped in the MMSNs to kill cancer cells. It was found that with the aid of an external magnetic field, drug loaded MMSNs showed high contrast in MR imaging in vivo and exhibited magnetically enhanced accumulation in the cancer site, leading to significant inhibition of cancer growth with minimal side effects. This multifunctional MMSN will find great potential as a theranostic nanoplatform for cancer treatment.

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self-Synergistic Tumor Targeting Therapy.

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self-synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell-penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor-made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self-synergistically therapeutic capacity opens new avenues for cancer therapy.