Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy.

A Simple Binary Supramolecular Co-Assembly Platform for Enhanced Tumor Imaging and Therapy.

The primary challenges in tumor imaging and therapy revolve around improving targeting efficiency, enhancing probe/drug delivery efficacy, and minimizing off-target signals and toxicity. Although various carriers have been developed, many are difficult to synthesize, costly, and not universally applicable. Furthermore, numerous carriers exhibit limited delivery rates in solid tumors, particularly larger nanocarriers. To address these challenges, a simple binary co-assembly drug delivery platform has been designed using the readily synthesized small molecule Cys(SEt)-Lys-CBT (CKCBT) as the self-assembly building block. CKCBT can effectively penetrate tumor cells due to its positively charged Lys side chain and small size. Upon glutathione reduction, CKCBT co-assembles with Nile red or Chlorin e6 to form nanofibers inside tumor cells. This enables their specific accumulation in tumor cells rather than normal cells and extends their exposure time, resulting in precise and enhanced tumor imaging and treatment. Hence, this uncomplicated and highly efficient binary co-assembly drug delivery platform can be easily adapted to a broad spectrum of probes and drugs, presenting a novel approach for advancing clinical diagnosis and therapy.

Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment.

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives.

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation of dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and the loss of iron-sulfur cluster proteins, ultimately resulting in proteotoxic stress and triggering cell death. Recently, cuproptosis has garnered significant interest in tumor research due to its potential as a crucial therapeutic strategy against cancer. In this review, we summarized the cellular and molecular mechanisms of cuproptosis and its relationship with other types of cell death. Additionally, we reviewed the current drugs or strategies available to induce cuproptosis in tumor cells, including Cu ionophores, small compounds, and nanomedicine. Furthermore, we targeted cell metabolism and specific regulatory genes in cancer therapy to enhance tumor sensitivity to cuproptosis. Finally, we discussed the feasibility of targeting cuproptosis to overcome tumor chemotherapy and immunotherapy resistance and suggested future research directions. This study suggested that targeting cuproptosis could open new avenues for developing tumor therapy.

Hierarchically Micro-, Meso-, and Macro-Porous MOF Nanosystems for Localized Cross-Scale Dual-Biomolecule Loading and Guest-Carrier Cooperative Anticancer Therapy.

Mass transfer of bulky molecules, e.g., bioenzymes, particularly for cross-scale multibiomolecules, imposes serious challenges for microporous metal-organic frameworks (MOFs). Here, we create a hierarchically porous MOF heterostructure featuring highly region-ordered micro-, meso-, and macro-pores by growing a microporous ZIF-8 shell onto a hollow Prussian blue core through an epitaxial growth strategy. This allows for localized loading of large bioenzyme glucose oxidase (GOx) and small drug 5-fluorouracil (5-FU) within specific pores simultaneously and triggers unique guest-carrier cooperative anticancer capabilities. The stable ZIF-8 outer layer effectively blocks the core pores, preventing the undesired leakage of GOx into normal tissues. The acidity-induced ZIF-8 degradation gradually releases Zn2+ and loaded 5-FU for chemotherapy under acidic tumor microenvironments. With the loss of the shielding effect of the ZIF-8 coating, the released GOx depletes intratumoral glucose (Glu) for starvation therapy. Notably, an accelerated cascade reaction occurs between ZIF-8 decomposition and GOx release, facilitated by the modulator factor of Glu. This culminates in the realization of synergistic cancer therapy, as comprehensively demonstrated by in vitro and in vivo experiments, as well as transcriptome sequencing analyses. Our work not only introduces a hierarchically porous MOF heterostructure with highly region-ordered pores but also provides a perspective for guest-carrier cooperative anticancer therapy.

Antagonist anti-LIF antibody derived from naive human scFv phage library inhibited tumor growth in mice.

BACKGROUND: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models. RESULTS: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue. CONCLUSIONS: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.

Research progress in tumor therapy of carrier-free nanodrug.

Carrier-free nanodrugs are a novel type of drug constructed by the self-assembly of drug molecules without carrier involvement. They have the characteristics of small particle size, easy penetration of various barriers, targeting tumors, and efficient release. In recent years, carrier-free nanodrugs have become a hot topic in tumor therapy as they solve the problems of low drug loading, poor biocompatibility, and low uptake efficiency of carrier nanodrugs. A series of recent studies have shown that carrier-free nanodrugs play a vital role in the treatment of various tumors, with similar or better effects than carrier nanodrugs. Based on the literature published in the past decades, this paper first summarizes the recent progress in the assembly modes of carrier-free nanodrugs, then describes common therapeutic modalities of carrier-free nanodrugs in tumor therapy, and finally depicts the existing challenges along with future trends of carrier-free nanodrugs. We hope that this review can guide the design and application of carrier-free nanodrugs in the future.

Natural-source payloads used in the conjugated drugs architecture for cancer therapy: Recent advances and future directions.

Drug conjugates are obtained from tumor-located vectors connected to cytotoxic agents via linkers, which are designed to deliver hyper-toxic payloads directly to targeted cancer cells. These drug conjugates include antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), nucleic acid aptamer-drug conjugates (ApDCs), and virus-like drug conjugate (VDCs), which show great therapeutic value in the clinic. Drug conjugates consist of a targeting carrier, a linker, and a payload. Payloads are key therapy components. Cytotoxic molecules and their derivatives derived from natural products are commonly used in the payload portion of conjugates. The ideal payload should have sufficient toxicity, stability, coupling sites, and the ability to be released under specific conditions to kill tumor cells. Microtubule protein inhibitors, DNA damage agents, and RNA inhibitors are common cytotoxic molecules. Among these conjugates, cytotoxic molecules of natural origin are summarized based on their mechanism of action, conformational relationships, and the discovery of new derivatives. This paper also mentions some cytotoxic molecules that have the potential to be payloads. It also summarizes the latest technologies and novel conjugates developed in recent years to overcome the shortcomings of ADCs, PDCs, SMDCs, ApDCs, and VDCs. In addition, this paper summarizes the clinical trials conducted on conjugates of these cytotoxic molecules over the last five years. It provides a reference for designing and developing safer and more efficient conjugates.

Predicting anti-tumor efficacy of multi-functional nanomedicine on decellularized hepatocellular carcinoma-on-a-chip.

Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe3O4)-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening.

Mn-ZIF nanozymes kill tumors by generating hydroxyl radical as well as reversing the tumor microenvironment.

Tumor tissues are well known for their unique high hydrogen peroxide (H2O2) microenvironment. How to exploit this tumor microenvironment for tumor cell killing is a question. In this study, a Mn-doped metal-organic framework (Mn-ZIF) was constructed. It possesses good peroxidase (POD) activity, which can oxidize tumor-localized H2O2 into hydroxyl radicals (·OH), that possesses the ability to directly kill tumor cells. More surprisingly, in vivo experiments the researchers not only observed the tumor-killing effect of Mn-ZIF, but also found it changes in macrophage phenotype in the tumor region. There was an increase in macrophage polarization towards the M1 subtype. This suggests that the tumor-killing effect of Mn-ZIF not only comes from its POD activity, but also regulates the immune microenvironment in the tumor region. In conclusion, the preparation of Mn-ZIF provides a new way for comprehensive tumor therapy.

Near-Infrared Laser-Switching DNA Phase Separation Nanoinducer for Glioma Therapy.

DNA phase separation participates in chromatin packing for the modulation of gene transcription, but the induction of DNA phase separation in living cells for disease treatment faces huge challenges. Herein, we construct a Ru(II)-polypyridyl-loaded upconversion nanoplatform (denoted as UCSNs-R) to achieve the manipulation of DNA phase separation and production of abundant singlet oxygen (1O2) for efficient treatment of gliomas. The utilization of the UCSN not only facilitates high loading of Ru(II)-polypyridyl complexes (RuC) but also promotes the conversion of near-infrared (NIR) laser to ultraviolet light for efficient 1O2 generation. The released RuC exhibit DNA "light-switch" behavior and high DNA binding affinity that induce phase separation of DNA in living cells, thus resulting in DNA damage and suppressing tumor-cell growth. In vivo investigation demonstrates the high capability of UCSNs-R in inhibiting tumor proliferation under NIR laser illumination. This work represents a paradigm for designing a DNA phase separation nanoinducer through integration of the UCSN with Ru(II)-polypyridyl-based complexes for efficient therapy of gliomas.

Self-initiated nano-micelles mediated covalent modification of mRNA for labeling and treatment of tumors.

As a promising gene therapy strategy, controllable small molecule-mRNA covalent modification in tumor cells could be initiated by singlet oxygen (1O2) to complete the modification process. However, in vivo generation of 1O2 is usually dependent on excitation of external light, and the limited light penetration of tissues greatly interferes the development of deep tumor phototherapy. Here, we constructed a tumor-targeting nano-micelle for the spontaneous intracellular generation of 1O2 without the need for external light, and inducing a high level of covalent modification of mRNA in tumor cells. Luminal and Ce6 were chemically bonded to produce 1O2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H2O2) in the tumor microenvironment. The sufficient 1O2 oxidized the loaded furan to highly reactive dicarbonyl moiety, which underwent cycloaddition reaction with adenine (A), cytosine (C) or guanine (G) on the mRNA for interfering with the tumor cell protein expression, thereby inhibiting tumor progression. In vitro and in vivo experiments demonstrated that this self-initiated gene therapy nano-micelle could induce covalent modification of mRNA by 1O2 without external light, and the process could be monitored in real time by fluorescence imaging, which provided an effective strategy for RNA-based tumor gene therapy.

V-doped MoS2 nanozymes providing reactive oxygen species and depleting glutathione for photothermally-enhanced nanocatalytic therapy.

Introduction: The tumor microenvironment and multidrug resistance of tumor cells seriously impair the activity of the nanozymes. Methods: Herein, a polyethylene glycol (PEG)-modified vanadium-doped molybdenum disulfide (V-MoS2@PEG) nanozymes were constructed to enhance anti-tumor activity through multi-enzymatic catalysis and photothermal effect with simultaneous reactive oxygen species replenishment and glutathione depletion. Results and discussion: V-MoS2@PEG nanosheets exerted peroxidase activity by causing molybdenum ion (Mo4+) to react with hydrogen peroxide to form toxic hydroxyl radicals (·OH). Meanwhile, the V-doping can deplete glutathione avoiding ·OH consumption. In addition, the high heat generated by V-MoS2@PEG nanozymes under near-infrared laser irradiation brought about a desirable local temperature gradient, which produced an enhanced catalytic effect by promoting band bending. Furthermore, the photothermally inspired polarized charge increased the permeability of the tumor cell membrane and promoted further aggregation of the nanozymes, which realized the combination of photothermal therapy with multi-enzymatic catalysis, solved the problem of multi-enzyme catalysis, and improved the anti-tumor efficiency.

The Rational Engineered Bacteria Based Biohybrid Living System for Tumor Therapy.

Living therapy based on bacterial cells has gained increasing attention for their applications in tumor treatments. Bacterial cells can naturally target to tumor sites and active the innate immunological responses. The intrinsic advantages of bacteria attribute to the development of biohybrid living carriers for targeting delivery toward hypoxic environments. The rationally engineered bacterial cells integrate various functions to enhance the tumor therapy and reduce toxic side effects. In this review, the antitumor effects of bacteria and their application are discussed as living therapeutic agents across multiple antitumor platforms. The various kinds of bacteria used for cancer therapy are first introduced and demonstrated the mechanism of antitumor effects as well as the immunological effects. Additionally, this study focused on the genetically modified bacteria for the production of antitumor agents as living delivery system to treat cancer. The combination of living bacterial cells with functional nanomaterials is then discussed in the cancer treatments. In brief, the rational design of living therapy based on bacterial cells highlighted a rapid development in tumor therapy and pointed out the potentials in clinical applications.

Nanomaterial-assisted oncolytic bacteria in solid tumor diagnosis and therapeutics.

Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.

Beyond surgery: Overcoming postoperative depression in cancer patients.

Depression is a common occurrence among cancer patients, and it significantly impacts their clinical outcomes and quality of life, with a high incidence during anti-tumor treatment or after surgery. The association between surgery and depression is the result of the interaction of various factors, including physiological, psychological, and social factors, all of which are intertwined and make patients susceptible to depression after surgical treatment. Postoperative depression has a significant negative impact on many aspects of cancer patients, and it requires timely identification and intervention to improve the overall outcome.

Nickel atom-clusters nanozyme for boosting ferroptosis tumor therapy.

The translation of Fe-based agents for ferroptosis tumor therapy is restricted by the unstable iron valence state, the harsh catalytic environment, and the complex tumor self-protection mechanism. Herein, we developed a stable nickel-based single-atom-metal-clusters (NSAMCs) biocatalyst for efficient tumor ferroptosis therapy. NSAMCs with a nanowire-like nanostructure and hydrophilic functional groups exhibit good water-solubility, colloidal stability, negligible systemic toxicity, and target specificity. In particular, NSAMCs possess excellent peroxidase-like and glutathione oxidase-like activities through the synergistic influence between metal clusters and single atoms. The dual-enzymatic performance enables NSAMCs to synergistically promote efficient ferroptosis of cancer cells through lipid peroxidization aggregation and glutathione peroxidase 4 inactivation. Importantly, NSAMCs highlight the boost of ferroptosis tumor therapy via the synergistic effect between single-atoms and metal clusters, providing a practical and feasible paradigm for further improving the efficiency of ferroptosis tumor treatment.

Preliminary investigation of nitric oxide release from upconverted nanoparticles excited at 808 nm near-infrared for brain tumors.

Upconverted UCNPs@mSiO2-NH2 nanoparticles were synthesized via thermal decomposition while employing the energy resonance transfer principle and the excellent near-infrared (NIR) light conversion property of up-conversion. The 808 nm NIR-excited photocontrolled nitric oxide (NO) release platform was successfully developed by electrostatically loading photosensitive NO donor Roussin's black salt (RBS) onto UCNPs@mSiO2-NH2, enabling the temporal, spatial, and dosimetric regulation of NO release for biological applications of NO. The release of NO ranged from 0.015⁓0.099 mM under the conditions of 2.0 W NIR excitation power, 20 min of irradiation time, and UCNPs@mSiO2-NH2&RBS concentration of 0.25⁓1.25 mg/mL. Therefore, this NO release platform has an anti-tumor effect. In vitro experiments showed that under the NIR light, at concentrations of 0.3 mg/mL and 0.8 mg/mL of UCNPs@mSiO2-NH2&RBS, the activity of glioma (U87) and chordoma (U-CH1) cells, as measured by CCK8 assay, was reduced to 50 %. Cell flow cytometry and Western Blot experiments showed that NO released from UCNPs@mSiO2-NH2&RBS under NIR light induced apoptosis in brain tumor cells. In vivo experiments employing glioma and chordoma xenograft mouse models revealed significant inhibition of tumor growth in the NIR and UCNPs@mSiO2-NH2&RBS group, with no observed significant side effects in the mice. Therefore, NO released by UCNPs@mSiO2-NH2&RBS under NIR irradiation can be used as a highly effective and safe strategy for brain tumor therapy.

Advancing Tumor Therapy: Development and Utilization of Protein-Based Nanoparticles.

Protein-based nanoparticles (PNPs) in tumor therapy hold immense potential, combining targeted delivery, minimal toxicity, and customizable properties, thus paving the way for innovative approaches to cancer treatment. Understanding the various methods available for their production is crucial for researchers and scientists aiming to harness these nanoparticles for diverse applications, including tumor therapy, drug delivery, imaging, and tissue engineering. This review delves into the existing techniques for producing PNPs and PNP/drug complexes, while also exploring alternative novel approaches. The methods outlined in this study were divided into three key categories based on their shared procedural steps: solubility change, solvent substitution, and thin flow methods. This classification simplifies the understanding of the underlying mechanisms by offering a clear framework, providing several advantages over other categorizations. The review discusses the principles underlying each method, highlighting the factors influencing the nanoparticle size, morphology, stability, and functionality. It also addresses the challenges and considerations associated with each method, including the scalability, reproducibility, and biocompatibility. Future perspectives and emerging trends in PNPs' production are discussed, emphasizing the potential for innovative strategies to overcome current limitations, which will propel the field forward for biomedical and therapeutic applications.

A strategy of "adding fuel to the flames" enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy.

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry (i.e., "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.