Harnessing Nature's ingenuity to engineer butterfly-wing-inspired photoactive nanofiber patches for advanced postoperative tumor treatment.

Postoperative tumor treatment necessitates a delicate balance between eliminating residual tumor cells and promoting surgical wound healing. Addressing this challenge, we harness the innovation and elegance of nature's ingenuity to develop a butterfly-wing-inspired photoactive nanofiber patch (WingPatch), aimed at advancing postoperative care. WingPatch is fabricated using a sophisticated combination of electrostatic spinning and spraying techniques, incorporating black rice powder (BRP) and konjac glucomannan (KGM) into a corn-derived polylactic acid (PLA) nanofiber matrix. This fabrication process yields a paclitaxel-infused porous nanofiber architecture that mirrors the delicate patterns of butterfly wings. Meanwhile, all-natural composites have been selected for their strategic roles in postoperative recovery. BRP offers the dual benefits of photothermal therapy and antibacterial properties, while KGM enhances both antibacterial effectiveness and tissue regeneration. Responsive to near-infrared light, WingPatch ensures robust tissue adhesion and initiates combined photothermal and chemotherapeutic actions to effectively destroy residual tumor cells. Crucially, it simultaneously prevents infections and promotes wound healing throughout the treatment process. Its effectiveness has been confirmed by animal studies, and WingPatch significantly improves treatment outcomes in both breast and liver tumor models. Thus, WingPatch exemplifies our dedication to leveraging natural world's intricate patterns and inventiveness to propel postoperative care forward.

Bacteria-based cascade in situ near-infrared nano-optogenetically induced photothermal tumor therapy.

Rationale: Optogenetically engineered facultative anaerobic bacteria exhibit a favorable tendency to colonize at solid tumor sites and spatiotemporally-programmable therapeutics release abilities, attracting extensive attention in precision tumor therapy. However, their therapeutic efficacy is moderate. Conventional photothermal agents with high tumor ablation capabilities exhibit low tumor targeting efficiency, resulting in significant off-target side effects. The combination of optogenetics and photothermal therapy may offer both tumor-targeting and excellent tumor-elimination capabilities, which unfortunately has rarely been investigated. Herein, we construct a bacteria-based cascade near-infrared optogentical-photothermal system (EcNαHL-UCNPs) for enhanced tumor therapy. Methods: EcNαHL-UCNPs consists of an optogenetically engineered Escherichia coli Nissle 1917 (EcN) conjugated with lanthanide-doped upconversion nanoparticles (UCNPs), which are capable of locally secreting α-hemolysin (αHL), a pore-forming protein, in responsive to NIR irradiation. Anti-tumor effects of EcNαHL-UCNPs were determined in both H22 and 4T1 tumors. Results: The αHL not only eliminates tumor cells, but more importantly disrupts endothelium to form thrombosis as an in situ photothermal agent in tumors. The in situ formed thrombosis significantly potentiates the photothermic ablation of H22 tumors upon subsequent NIR light irradiation. Besides, αHL secreted by EcNαHL-UCNPs under NIR light irradiation not only inhibits 4T1 tumor growth, but also suppresses metastasis of 4T1 tumor via inducing the immune response. Conclusion: Our studies highlight bacteria-based cascade optogenetical-photothermal system for precise and effective tumor therapy.

Co-delivery of PROTAC and siRNA via novel liposomes for the treatment of malignant tumors.

Targeted elimination of damaged or overexpressed proteins within the tumor serves a pivotal role in regulating cellular function and restraining tumor cell growth. Researchers have been striving to identify safer and more effective methods for protein removal. Here, we propose the synergistic employment of a small molecule degrading agent (PROTAC) and siRNA to attain enhanced protein clearance efficiency and tumor therapeutic effects. Co-delivery liposomes were prepared to facilitate the efficient encapsulation of PROTAC and siRNA. Specifically, the cationic liposome significantly improved the solubility of the insoluble PROTAC (DT2216). The cationic polymer (F-PEI) achieved efficient encapsulation of the nucleic acid drug, thereby promoting endocytosis and enhancing the therapeutic impact of the drug. Both in vivo and in vitro experiments demonstrated remarkable degradation of target proteins and inhibition of tumor cells by the co-delivery system. In conclusion, the co-delivery liposomes furnished a nano-delivery system proficient in effectively encapsulating both hydrophilic and hydrophobic drugs, thereby presenting a novel strategy for targeted combination therapy in treating tumors.

A Highly Tumor Permeating DNA Nanoplatform for Efficient Remodeling of Immunosuppressive Tumor Microenvironments.

Immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure-based nanoplatform with striking tumor-penetrating capability for targeted remodeling of immunosuppressive tumor microenvironment in vivo. In our design, chemo-immunomodulator (gemcitabine) can be precisely grafted in DNA sequences via a reactive oxygen species (ROS)-sensitive linker. After self-assembly, the gemcitabine-grafted DNA structure can site-specifically organize legumain-activatable melittin pro-peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi-type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.

Targeting the Tumor Epigenetic Regulator SETDB1 for Tumor Therapy.

Epigenetic alterations are implicated in the early stages of tumorigenesis and are widely recognized as a ubiquitous phenomenon in cancer development. Aberrant epigenetic modifications can alter the expression of target genes, induce heterochromatin formation, and gradually drive normal cells towards immortalized tumor cells with significant consequences. SETDB1 (SET domain bifurcated histone lysine methyltransferase 1), a typical histone me-thyltransferase, promotes the formation of heterochromatin and inhibits the transcription of genes by modifying the methylation of lysine 9 of histone 3. SETDB1 is usually highly ex-pressed in tumors with high copy numbers, accompanied by poor prognosis and low patient survival rates, which is a typical case of abnormal epigenetic modification. We discuss the mechanism of SETDB1 in a variety of cancers and review the epigenetic inhibitors that have been reported in recent years, along with their anti-tumor effects. In addition, we summarize the role of SETDB1 in a variety of diseases and cell functions.

Advances in ferroptosis in head and neck cancer (Review).

Ferroptosis is an iron-dependent form of cell death that was discovered in 2012. It encompasses the coordinated orchestration of three fundamental biological pathways: Iron homeostasis, glutathione regulation and lipid metabolism. Head and neck cancer (HNC) is a heterogeneous group of cancers occurring on the mucosal surfaces of the upper respiratory and digestive tracts. Head and neck squamous cell carcinoma is the most common type of HNC, accounting for >90% of HNC cases, and has high morbidity and mortality rates. Despite improvements in diagnosis and treatment, the 5-year survival rate hovers at a dismal 50-60%, with recurrence afflicting nearly 30% of patients, highlighting the inadequacies of currently available treatments. Of note, research exploring the nexus between ferroptosis and HNC remains scarce; however, the present review endeavors to synthesize current knowledge surrounding ferroptosis. The present review elaborated on the normal physiological role of ferroptosis and discussed its potential involvement in HNC pathogenesis. Therapeutic strategies and prognostic paradigms for HNC that target ferroptosis were also reviewed. This review aims to provide direction to catalyze future investigations into ferroptosis in HNC.

Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution.

Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Activatable Fluorescence and Bio/Chemiluminescence Probes for Aminopeptidases: From Design to Biomedical Applications.

Aminopeptidases are exopeptidases that catalyze the cleavage of amino acid residues from the N-terminal fragment of protein or peptide substrates. Owing to their function, they play important roles in protein maturation, signal transduction, cell-cycle control, and various disease mechanisms, notably in cancer pathology. To gain better insights into their function, molecular imaging assisted by fluorescence and bio/chemiluminescence probes has become an indispensable method to their superiorities, including excellent sensitivity, selectivity, and real-time and noninvasive imaging. Numerous efforts are made to develop activatable probes that can effectively enhance efficiency and accuracy as well as minimize the side effects. This review is classified according to the type of aminopeptidases, summarizing some recent works on the design, work mechanism, and sensing, imaging, and theranostic performance of their activatable probe. Finally, the current challenges are outlined in developing activatable probes for aminopeptidases and provide possible solutions for future advancements.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.