Achieving Immune Activation by Suppressing the IDO1 Checkpoint with Sono-Targeted Biobromination for Antitumor Combination Immunotherapy.

Indoleamine-2,3-dioxygenase-1 (IDO1) pathogenically suppresses immune cell infiltration and promotes tumor cell immune escape by overmetabolizing tryptophan to N-formyl kynurenine in the tumor microenvironment (TME). However, it remains challenging for IDO1 immune checkpoint inhibitors to achieve a significant potency of progression-free survival. Here, we developed a breakthrough in IDO1 inhibition by sono-targeted biobromination reaction using immunostimulating hypobromic-P-phenylperoxydibenzoic acid-linked metallic organic framework nanomedicine (H-MOF NM) to remodel the TME from debrominated hypoxia into hypobromated normoxia and activate the IDO1 immune pathway with in vitro and in vivo remarkable antitumor efficacy. H-MOF NM contains Br+ and O- active ingredients with an enlarged band gap to deactivate IDO1 through an innovative biochemical mechanism, taking control over brominating IDO1 amino acid residues at the active sites in the remodeled TME and subsequently activating the immune response, including DC maturation, T-cell activation, and macrophage polarization. Importantly, the H-MOF NM achieves multiple immune responses with high tumor regression potency by combination sono-immunotherapy. This study describes an excellent IDO1 inhibition strategy through the development of immune biobrominative H-MOF nanomedicine and highlights efficient combination immunotherapy for tumor treatment.

Inhibition of thioredoxin reductase and upregulation of apoptosis genes for effective anti-tumor sono-chemotherapy using a meso-organosilica nanomedicine.

The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.

Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity.

Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer-associated fibroblasts (CAFs) show multiple tumor-promoting effects and can induce tumor immune evasion and drug-resistance. Regulating CAFs can be a potential strategy to augment systemic anti-tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs' tumor-promoting and immune-suppressive phenotypes. Accordingly, a controllable and TME-responsive hydrogen therapy based on a CaCO3 nanoparticles-coated magnesium system (Mg-CaCO3) is developed. The hydrogen therapy by Mg-CaCO3 can not only directly kill tumor cells, but also inhibit pro-tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4+ T cells. As implanted in situ, Mg-CaCO3 can significantly suppress tumor growth, turn the "cold" primary tumor into "hot", and stimulate systematic anti-tumor immunity, which is confirmed by the bilateral tumor transplantation models of "cold tumor" (4T1 cells) and "hot tumor" (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti-tumor immune stimulating strategy by remodeling tumor stromal microenvironment.

Integrated organosilica nanomedicine enables sonoimaging, sonochemistry and antitumor sonodynamic therapy.

Sonography with its non-invasive and deep tissue-penetrating characteristics, not only contributes to promising developments in clinical disease diagnosis but also obtains acknowledgments as a prospective therapeutic approach in the field of tumor treatment. However, it remains a challenge for sonography simultaneously to achieve efficient imaging and therapeutic functionality. Here, we present an innovative integrated diagnosis and treatment paradigm by developing the nanomedicine of percarbamide-bromide-mesoporous organosilica spheres (MOS) with RGD peptide modification (PBMR) by loading percarbamide and bromide in MOS which were prepared by a one-step O/W microemulsion method. The PBMR nanomedicine effectively modifies the tumor acoustic environment to improve sonoimaging efficacy and induces sonochemical reactions to enhance the production of reactive oxygen species (ROS) for tumor treatment efficiency under sonography. The combination of PBMR nanomedicine and SDT achieved multiple ROS generation through the controlled sonochemical reactions and significantly boosted the potency of sonodynamic therapy and induced significant tumor regression with non-invasive tissue penetrability and minimizing damage to healthy tissues. Simultaneously, the generation of oxygen gas in the sonochemical process augments ultrasound reflection, resulting in a 4.9-fold increase in imaging grayscale. Our research establishes an effective platform for the synergistic integration of sonoimaging and sonodynamic antitumor therapy, offering a novel approach for precise antitumor treatment in the potential clinical applications.

Bimetallic Organic Frameworks of High Piezovoltage for Sono-Piezo Dynamic Therapy.

Piezoelectric materials produce charges to directly act on cancer medium or promote the generation of reactive oxygen species (ROS) for novel tumor therapy triggered by sonography. Currently, piezoelectric sonosensitizers are mainly used to catalyze ROS generation by the band-tilting effect for sonodynamic therapy. However, it remains a challenge for piezoelectric sonosensitizers to produce high piezovoltages to overcome the bandgap barrier for direct charge generation. Herein, Mn-Ti bimetallic organic framework tetragonal nanosheets (MT-MOF TNS) are designed to produce high piezovoltages for novel sono-piezo (SP)-dynamic therapy (SPDT) with remarkable antitumor efficacy in vitro and in vivo. The MT-MOF TNS comprise non-centrosymmetric secondary building units of Mn-Ti-oxo cyclic octamers with charge heterogeneous components for piezoelectricity. The MT-MOF TNS promotes strong sonocavitation to induce piezoelectric effect with a high SP voltage (2.9 V) in situ, to directly excite charges, which is validated by SP-excited luminescence spectrometry. The SP voltage and charges depolarize the mitochondrial and plasma membrane potentials and cause ROS overproduction and serious tumor cell damage. Importantly, MT-MOF TNS can be decorated with targeting molecules and chemotherapeutics for more severe tumor regression by combining SPDT with chemodynamic therapy and chemotherapy. This report develops a fascinating MT-MOF piezoelectric nano-semiconductor and provides an efficient SPDT strategy for tumor treatment.

Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration Via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression.

Intervertebral disc degeneration (IVDD)-induced lower back pain (LBP) is a common problem worldwide. The underlying mechanism is partially accredited to ferroptosis, based on sequencing analyses of IVDD patients from the gene expression omnibus (GEO) databases. In this study, it is shown that polydopamine nanoparticles (PDA NPs) inhibit oxidative stress-induced ferroptosis in nucleus pulposus (NP) cells in vitro. PDA NPs scavenge reactive oxygen species (ROS), chelate Fe2+ to mitigate iron overload, and regulate the expression of iron storage proteins such as ferritin heavy chain (FHC), ferritin, and transferrin receptor (TFR). More importantly, PDA NPs co-localize with glutathione peroxidase 4 (GPX4) around the mitochondria and suppress ubiquitin-mediated degradation, which in turn exerts a protective function via the transformation and clearance of phospholipid hydroperoxides. PDA NPs further down-regulate malondialdehyde (MDA) and lipid peroxide (LPO) production; thus, antagonizing ferroptosis in NP cells. Moreover, PDA NPs effectively rescue puncture-induced degeneration in vivo by targeting ferroptosis and inhibiting GPX4 ubiquitination, resulting in the upregulation of antioxidant pathways. The findings offer a new tool to explore the underlying mechanisms and a novel treatment strategy for IVDD-induced LBP.

Activatable nanomedicine for overcoming hypoxia-induced resistance to chemotherapy and inhibiting tumor growth by inducing collaborative apoptosis and ferroptosis in solid tumors.

Hypoxia has been firmly correlated to the drug resistance of solid tumors. Alleviation of hypoxia by tumor reoxygenation is expected to sensitize the chemotherapy toward solid tumors. Alternatively, ferroptosis provides a therapeutic strategy to overcome apoptotic resistance and multidrug resistance of solid tumors, collaboratively strengthening the chemotherapy toward hypoxic tumors. Herein, an ultrasound (US)-activatable nanomedicine was developed for overcoming hypoxia-induced resistance to chemotherapy and efficiently inhibiting tumor growth by inducing sensitized apoptosis and collaborative ferroptosis of tumor cells. This nanomedicine was constructed by integrating ferrate and doxorubicin into biocompatible hollow mesoporous silica nanoplatforms, followed by assembling a solid-liquid phase-change material of n-heneicosane. The US-induced mild hyperthermia initiates the phase change of n-heneicosane, enabling US-activated co-release of ferrate and doxorubicin. Results reveal that the released ferrate effectively reacts with water as well as the over-expressed hydrogen peroxide and glutathione in tumor cells, achieving tumor-microenvironment-independent reoxygenation and glutathione-depletion in tumors. The reoxygenation down-regulates expressions of hypoxia-inducible factor 1α and multidrug resistance gene/transporter P-glycoprotein in tumor cells, sensitizing the apoptosis-based doxorubicin chemotherapy. More importantly, exogenous iron metabolism from the nanomedicine initiates intracellular Fenton reactions, leading to reactive oxygen species overproduction and iron-dependent ferroptotic death of tumor cells. Furthermore, the glutathione-depletion inactivates the glutathione peroxidase 4 (GPX4, a critical regulatory target in ferroptosis), inhibiting the reduction of lipid peroxides and reinforcing the ferroptotic cell death. The sensitized chemotherapy together with the iron-dependent ferroptosis of tumor cells play a synergistic role in boosting the growth suppression of hypoxic osteosarcoma in vivo. Additionally, the nanomedicine acts as a nanoprobe for in vivo photoacoustic imaging and glutathione tracking, showing great potential as theranostic agents for hypoxic solid tumors treatment.

Stereoselective and Site-Specific Allylic Alkylation of Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis.

We report a stereoselective and site-specific allylic alkylation of Schiff base activated amino acids and small peptides via a Pd/Cu dual catalysis. A range of noncoded α,α-dialkyl α-amino acids were easily synthesized in high yields and with excellent enantioselectivities (up to >99% ee). Furthermore, a direct and highly stereoselective synthesis of small peptides with enantiopure α-alkyl or α,α-dialkyl α-amino acids residues incorporated at specific sites was accomplished using this dual catalyst system.

Lysosomes activating chain reactions against cancer cells with a pH-switched prodrug/procatalyst co-delivery nanosystem.

Conventional chemotherapy uses potent toxic drugs to destroy cancer cells and always causes severe systemic toxicity in patients. In this respect, a smart and pH-switched prodrug/procatalyst co-delivery nanosystem is developed which is non-toxic toward normal cells and is inert during its delivery in the vasculature, while responsively functions in acidic lysosomes inside cancer cells. Synthetically, non-toxic artemisinin (ART) was used as the prodrug and loaded into the inner space of hollow mesoporous silica (HMS) nanoparticles (NPs). Subsequently, Fe3O4 NPs were efficiently capped onto pore outlets of HMS via acid labile acetal linkers (ART@HMS-Fe3O4). ART@HMS-Fe3O4 was stable under neutral conditions (pH 7.4) with almost no leakage of ART. Upon exposure to the acidic lysosomal compartment (pH 3.8-5.0) in cells, the acetal linkers were hydrolyzed which led to sustained release of both ART and Fe3O4 NPs. Under the activation of the lysosomal environment, the liberated Fe3O4 NPs were metabolized to free iron ions and catalyzed the generation of high amounts of free radicals from the released ART in cells. In vitro cytotoxicity assay revealed excellent anticancer efficacy of this ART/Fe3O4 co-delivery nanosystem. The Fe3O4 NPs acted both as gatekeepers and procatalysts which inhibited ART from leakage during their delivery, while released ART and activated chain reactions to form free radicals in acidic lysosomes inside cancer cells. We visualize that this lysosomal environment-responsive ART@HMS-Fe3O4 nanosystem could serve as an efficient and desirable chemotherapeutic nanosystem for cancer therapy.

Efficient free radical generation against cancer cells by low-dose X-ray irradiation with a functional SPC delivery nanosystem.

Tumor hypoxia is a negative prognostic factor in cancer radiotherapy, due in part to its role in causing resistance to radiotherapy. It has attracted extensive critical attention to radiation sensitizers by using active oxygen to improve radiotherapy outcome. Active oxygen delivery functional materials are promising candidates to transport active oxygen to tumor cells. Herein, we report an oxygen delivery functional material by using hollow mesoporous silica nanoparticles (HMSNs) as carriers, synthesizing sodium percarbonate (SPC) in the channels and cavity of HMSNs (SPC@HMSNs) and coating polyacrylic acid (PAA) on the functional materials (SPC@HMSNs-PAA). SPC@HMSNs-PAA could release more SPC in a simulated tumor acidic microenvironment (pH ∼ 6.5), which can provide oxygen to improve radiotherapy outcome even under low energy X-ray irradiation. The events induce obvious overproduction of reactive oxygen radicals to kill cancer cells with a significant effect. Meanwhile, no obvious cytotoxicity was observed when SPC@HMSNs-PAA applied alone. The radiosensitization of SPC@HMSNs-PAA on cancer cells, even exposure to low-energy X-ray irradiation, may suggest promising application in radiotherapy.

Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem.

Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overproduction is thus greatly desirable for cancer therapy. To date, ROS production is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overproduction via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decomposition of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overproduction suggests promising applications in cancer treatments.

Controlled free radical generation against tumor cells by pH-responsive mesoporous silica nanocomposite.

Free radicals are toxic entities known to cause cellular damage and to mediate cell death. We herein develop a controlled free radical generation strategy for cancer therapy via pH-responsive release of benzoyl peroxide (BPO) in tumor cells and producing free radicals to mediate cell death. BPO as the free radical resource was encapsulated into a chitosan (Cs)-coated mesoporous silica nanocomposite (BPO@HMSNs-Cs). The mesoporous silica carrier improved the BPO solubility by preventing its crystallization and promoted its stability by inclusion. Chitosan imparted the nanocomposite pH-responsive BPO release capacity with enhanced BPO release in simulated acidic tumor media (pH 6.5) and minor release in simulated normal tissue media (pH 7.4). The enhanced free radical generation in tumor media further led to significantly higher cytotoxicity in the tumor at acidic pH 6.5 than at physiological pH 7.4. The free radical-mediated cytotoxicity of BPO@HMSNs-Cs was verified by the observation of free radical-induced green fluorescence in cells. This pH-responsive free radical generation nanocomposite may provide new opportunities for controlled drug delivery and cancer therapy.

Selective intracellular free radical generation against cancer cells by bioactivation of low-dose artesunate with a functionalized mesoporous silica nanosystem.

Excessive free radicals are noxious for living organisms and lead to cell death. Destruction of malignant cells by reactive free radicals has been widely used in cancer treatment. A key consideration is how to allow targeted free radical attack on cancer cells and avoid unwanted side-effects. Herein, we develop an efficient intracellular free radical generation strategy against cancer cells by delivering active ingredients into cancer cells, where free radicals are selectively generated by a lysosomal bioactivation process. Artesunate (ART), which is non-toxic to normal cells, was chosen as the free radical source and transported into cells with a hollow mesoporous silica-based delivery system (ART@HMS). To selectively activate the ART@HMS inside cancer cells, a high-bioactive Fe/O cluster-mesoporous silica nanosystem (Fe/O-MSN) was elaborately prepared. Under the bioactivation of the lysosome, the low-dose ART@HMS together with biocompatible Fe/O-MSN induced significant intracellular generation of toxic free radicals and efficient death of cancer cells. This selective intracellular free radical generation strategy is encouraging for its development into an effective low-cost cancer therapy.

Effective cancer cell killing by hydrophobic nanovoid-enhanced cavitation under safe low-energy ultrasound.

ß-Cyclodextrin (ß-CD)-capped mesoporous silica nanoparticles with hydrophobic internal nanovoids were prepared and used for effective cancer cell killing in synergistic combination with low-energy ultrasound (≤1.0 W cm(-2) , 1 MHz). The water-dispersible nanoparticles with hydrophobic internal nanovoids can be taken up by cancer cells and subsequently evoke a remarkable cavitation effect under irradiation with mild low-energy ultrasound (≤1.0 W cm(-2) , 1 MHz). A significant cancer cell killing effect was observed in cancer cells and in a mouse xenograft tumor model treated with the nanoagents together with the low-energy ultrasound, showing a distinct dependence on the concentration of nanoagents and ultrasound intensity. By contrast, an antitumor effect was not observed when either low-energy ultrasound or nanoagents were applied alone. These findings are significant as the technique promises a safe, low-cost, and effective treatment for cancer therapy.