There are tremendous challenges from both tumor and its therapeutic formulations affecting the effective treatment of tumor, including tumor recurrence, and complex multistep preparations of ...formulation. To address these issues, herein a simple and green approach based on the self-assembly of therapeutic agents including a photosensitizer (chlorine e6, Ce6) and a chemotherapeutic agent (doxorubicin, DOX) was developed to prepare carrier-free nanoparticles (NPs) with the ability to inhibit tumor recurrence. The designed NPs were formed by self-assembly of Ce6 and DOX associated with electrostatic, π–π stacking and hydrophobic interactions. They have a relatively uniform size of average 70 nm, surface charge of −20 mV and high drug encapsulation efficiency, which benefits the favorable accumulation of drugs at the tumor region through a potential enhanced permeability and retention (EPR) effect as compared to their counterpart of free Ce6 solution. In addition, they could eradiate tumors without recurrence in a synergistic way following one treatment cycle. Furthermore, the NPs are safe without any activation of inflammation or immune response in separated organs. Taken together, the rationale of these pure nanodrugs via the self-assembly approach might open an alternative avenue and give inspiration to fabricate new carrier-free nanodrugs for tumor theranostics, especially for two small molecular antitumor drugs with the aim of combinational antitumor therapy in a synergistic way.
Nanomedicine has revolutionized cancer therapeutic strategies but has not completely changed the outcomes of tricky tumors that evolve a sophisticated immunosuppressive tumor microenvironment (TME) ...such as acidification. Here, a metal-phenolic network-based nanocomplex embedded with lactate oxidase (LOX) and a mitochondrial respiration inhibitor atovaquone (ATO) was constructed for immunosuppressive TME remodeling and sonodynamic therapy (SDT). In this nanocomplex, the sonosensitizer chlorin e6-conjugated polyphenol derivative can induce the generation of tumor lethal reactive oxygen species upon ultrasound irradiation. LOX served as a catalyst for intracellular lactic acid exhaustion, and ATO led to mitochondrial dysfunction to decrease oxygen consumption. This nanocomplex reversed the tumor immunosuppressive status by alleviating tumor hypoxia and acidic TME, achieving the characteristic enhancement of SDT and the inhibition of tumor proliferation and metastasis.
Clinical translation of curcumin has been highly obstructed by the rapid degradation and poor tissue absorption of this agent. Herein, we report on the generation of supramolecular curcumin ...nanoagents through amino acid coordination driven self‐assembly to simultaneously increase the biological stability and tumor accumulation of curcumin. The biological stability of curcumin was significantly improved both through coordination and through molecular stacking. The sizes of these nanoagents can be readily manipulated to facilitate tumor accumulation. These favorable therapeutic features, together with high drug‐loading capacities and responses to pH and redox stimuli, substantially enhanced the antitumor activity of curcumin without discernible side effects. Hence, supramolecular curcumin nanoagents may hold promise in moving forward the clinical application of curcumin as an effective anticancer drug.
Special agents on the job: Supramolecular curcumin nanoagents were fabricated by amino acid coordination driven self‐assembly (see picture). The biological stability of curcumin was significantly improved through both coordination and molecular stacking in the nanoagents, the size of which could be readily manipulated. These favorable therapeutic features substantially enhanced the antitumor activity of curcumin without discernible side effects.
A multifunctional Ir6.2-Co(OH)2 nanozyme with a minimum of Ir content drives efficient cascade catalysis in TME and enables enhanced apoptosis-ferroptosis synergistic therapy.
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Noble ...metal nanozymes are promising therapeutic agents due to their good ability of reactive oxygen species generation in response to the tumor microenvironment (TME). Achieving optimal performance of noble metal nanozymes at a minimum dosage is crucial due to potential systemic biotoxicity. In this study, we report the successful anchoring of Ir nanoclusters on Co(OH)2 nanosheets with an Ir content of 6.2 wt% (denoted as Ir6.2-Co(OH)2), which exhibits remarkable peroxidase (POD)- and catalase (CAT)-like activities. The strong electronic interaction at the Ir-O-Co interface endows glutathione peroxidase (GSH-Px)-like activity to the composite, ensuring efficient generation of reactive oxygen species (ROS) and deactivation of glutathione peroxidase 4 (GPX4) by supplementing hydrogen peroxide (H2O2) and depleting glutathione (GSH). Both in vitro and in vivo evaluations demonstrate that Ir6.2-Co(OH)2 nanozymes significantly enhance antitumor efficacy through apoptosis-ferroptosis synergistic therapy. This study highlights the tremendous potential of leveraging strong electronic interactions between noble metals and oxides for modulating enzyme-like activities towards high-efficiency synergistic therapies.
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Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise ...active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.
The apoptosis-ferroptosis hybrid therapy opens up a new avenue for tumor eradication. Constructing efficient self-cascade platform is highly desired to enhance its therapeutic effect. Herein, we ...report on the synthesis of novel nanozyme consist of amorphous NiB alloy completely coated with an ultrathin layer of IrOx shell (A-NiB@C-IrOx). These core-shell nanoparticles exhibited peroxidase (POD)-, catalase (CAT)- and glutathione oxidase (GSH-OXD)-like properties for inducing self-cascade catalysis. Specifically, the amorphous IrOx shell with abundant active sites can effectively convert intratumor hydrogen peroxide (H2O2) to cytotoxic reactive oxygen species (ROS) and oxygen (O2). In presence of O2, amorphous NiB core and ultrathin IrOx shell collectively catalyze the oxidation of GSH to generate H2O2, which is subsequently converted to ROS and O2 by IrOx component. Thus, these enzymatic activities endow A-NiB@C-IrOx nanozymes with the ability of unceasing generation of ROS and O2 and depletion of GSH. In vitro and in vivo studies demonstrate a high therapeutic efficiency of A-NiB@C-IrOx nanozymes via apoptosis-ferroptosis combination therapy.
Apoptosis-ferroptosis hybrid therapy opens up new avenues for eradicating tumor cells. However, its actual therapeutic effect is still unsatisfied. Current efforts on this hybrid therapy focus on developing efficient self-cascade nanozymes to improve the efficiency of both ROS generation and GSH depletion. In this study, we constructed amorphous NiB alloy with a completed thin layer of IrOx shell (denoted as A-NiB@C-IrOx) for apoptosis-ferroptosis combination therapy. As expected, A-NiB@C-IrOx can trigger efficient cascade catalytic reactions to continuously generate ROS and consume GSH, finally inducing augmented apoptosis-ferroptosis combination therapy.
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A macromolecular drug , polysialic acid conjugated with folate (folate‐polySia), was developed by Ruikang Tang, Ben Wang et al. as an extracellular chemotherapy drug involving biomineralization for ...malignant tumor diseases in their Research Article on page 6509. The new type of drug combines with folate receptor and selectively induces biogenic mineral formation on tumor cells via absorbing calcium from the blood, resulting in the pathological calcification of tumors. Administration of folate‐polySia inhibits tumor growth and dramatically improved the survival rates of mice.
Recent studies in both mice and humans have suggested that gut microbiota could modulate tumor responsiveness to chemo- or immunotherapies. However, the underlying mechanism is not clear yet. Here, ...we found that gut microbial metabolites, especially butyrate, could promote the efficacy of oxaliplatin by modulating CD8+ T cell function in the tumor microenvironment. Butyrate treatment directly boosted the antitumor cytotoxic CD8+ T cell responses both in vitro and in vivo in an ID2-dependent manner by promoting the IL-12 signaling pathway. In humans, the oxaliplatin responder cancer patients exhibited a higher amount of serum butyrate than did non-responders, which could also increase ID2 expression and function of human CD8+ T cells. Together, our findings suggest that the gut microbial metabolite butyrate could promote antitumor therapeutic efficacy through the ID2-dependent regulation of CD8+ T cell immunity, indicating that gut microbial metabolites could be effective as a part of cancer therapy.
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•Gut microbial metabolites improve chemotherapy efficacy via regulating CD8+ T cells•The SCFA butyrate directly boosts the antitumor CD8+ T cell response via ID2•ID2 regulates the function of CD8+ T cells through IL-12 signaling•Butyrate supplementation improves the antitumor therapy efficacy
He et al. report that the gut microbial metabolite butyrate can directly modulate antitumor CD8+ T cell response and improve the chemotherapy efficacy through ID2-dependent IL-12 signaling, suggesting that manipulation of gut microbial metabolites could be effective as a part of cancer therapy.
Nanozymes, a class of nanomaterials mimicking the function of enzymes, have aroused much attention as the candidate in diverse fields with the arbitrarily tunable features owing to the diversity of ...crystalline nanostructures, composition, and surface configurations. However, the uncertainty of their active sites and the lower intrinsic deficiencies of nanomaterial‐initiated catalysis compared with the natural enzymes promote the pursuing of alternatives by imitating the biological active centers. Single‐atom nanozymes (SAzymes) maximize the atom utilization with the well‐defined structure, providing an important bridge to investigate mechanism and the relationship between structure and catalytic activity. They have risen as the new burgeoning alternative to the natural enzyme from in vitro bioanalytical tool to in vivo therapy owing to the flexible atomic engineering structure. Here, focus is mainly on the three parts. First, a detailed overview of single‐atom catalyst synthesis strategies including bottom‐up and top‐down approaches is given. Then, according to the structural feature of single‐atom nanocatalysts, the influence factors such as central metal atom, coordination number, heteroatom doping, and the metal–support interaction are discussed and the representative biological applications (including antibacterial/antiviral performance, cancer therapy, and biosensing) are highlighted. In the end, the future perspective and challenge facing are demonstrated.
Synthesis approaches including bottom‐up and top‐down strategies; catalysis modulation including central metal atom, coordination number, heteroatom doping, and the metal‐support interaction for activity and selectivity modulation of single‐atom nanozymes; and bioapplications in the biosensing, antibacterial, antiviral, and antitumor fields are reviewed.
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