Liposomal STAT3-Degrading PROTAC Prodrugs Promote Anti-Hepatocellular Carcinoma Immunity via Chemically Reprogramming Cancer Stem Cells.

Cancer stem cells (CSCs) with hyperactivated signal transducer and activator of transcription 3 (STAT3) are a major driver of hepatocellular carcinoma (HCC). Herein, we report a nanointegrative proteolysis-targeting chimera (PROTAC)-based STAT3 degradation strategy that enables efficient chemical reprogramming of HCC-associated CSCs, which potently inhibits CSC growth while evoking anti-HCC immune responses. The PROTAC prodrug was synthesized by conjugating the STAT3 binding domain (inS3) with a thioketal-caged E3 ligase ligand (VL-TK) via an oligo(ethylene glycol) linker (OEG) with tuned length and flexibility and encapsulating it in cRGD-modified cationic liposomes for CSC-targeted delivery while facilitating their lysosomal escape. The PROTAC prodrugs were activated by the upregulated ROS levels in CSCs and efficiently degraded STAT3 for chemical reprogramming, which would not only impair their stemness features but also remodel the immunosuppressive TME into an immunosupportive state to boost anti-HCC immunity. This strategy provides an approach for improving HCC treatment in clinics.

Tumor-Targeted Disruption of Lactate Transport with Reactivity-Reversible Nanocatalysts to Amplify Oxidative Damage.

Nanocatalytic tumor therapy is an emerging antitumor option that employs catalytically-active inorganic nanostructures to produce tumor-damaging reactive oxygen species. However, initiation of nanocatalytic reactions in the tumor intracellular environment is a challenge due to the reliance on acidic pH. By exploiting the pH-selective multifaceted catalytic activities of Prussian blue-based nanomaterials (PBNM) as well as the hyperglycolysis characteristics of tumors, it is demonstrated that blocking the monocarboxylate transporter 4 (MCT4)-mediated lactate effusion in tumor cells can reverse the pH gradient across the tumor cell membrane and cause rapid intracellular acidification as well as neutralization of the extracellular compartment, thus creating vulnerabilities for PBNM-based nanocatalytic therapies in situ while suppressing tumor stemness/metastasis in vivo. For this purpose, MCT4-inhibiting siRNAs are incorporated into reactivity-switchable PBNM-based nanocatalysts to initiate hydroxyl radical production. Meanwhile, ß-lapachone, a clinically-approved drug with H2 O2 -generating capabilities, is also integrated to sustain the nanocatalytic process. In contrast, the nanocatalyst shows no apparent toxicity to normal cells due to its catalase-like activities under neutral pH. This treatment strategy can inhibit tumor growth in mice at optimal safety as well as to suppress the cancer cell stemness and lung metastasis, suggesting the clinical translational potential of the findings.

Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug-Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy.

Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe2+ (DOX-Fe2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H2 O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.

Two-photon microscope using a fiber-based approach for supercontinuum generation and light delivery to a small-footprint optical head.

In this Letter, we report a low-cost, portable, two-photon excitation fluorescence microscopy imager that uses a fiber-based approach for both femtosecond supercontinuum (SC) generation and light delivery to the optical head. The SC generation is based on a tapered polarization-maintaining photonic crystal fiber that uses pre-chirped femtosecond narrowband pulses to generate a coherent SC spectrum with a bandwidth of approximately 300 nm. Using this approach, high-power, near-transform-limited, wavelength-selectable SC pulses are generated and directly delivered to the imaging optical head. Preliminary testing of this imager on brain slices is presented, demonstrating a high signal-to-noise ratio and sub-cellular imaging capabilities to a depth of approximately 200 µm. These results demonstrate the suitability of the technology for ex vivo and potentially in vivo cellular-level biomedical imaging applications.

Targeted inhibition of MCT4 disrupts intracellular pH homeostasis and confers self-regulated apoptosis on hepatocellular carcinoma.

The high lactate production rate in hepatocellular carcinoma cells (HCC) have a profound impact on their malignant properties. In adaptation to the enhanced lactate stress, lactate-effusing monocarboxylate transporter 4(MCT4) is usually overexpressed in a broad range of HCC subtypes. In this study, the MCT4-mediated lactate efflux in HCC was blocked using microRNA-145(miR-145), which would force the endogenously generated lactate to accumulate within tumor cells in a self-regulated manner, resulting in the acidification of the cytoplasmic compartment as well as partial neutralization for pH in the tumor extracellular environment. Evaluations on multiple representative HCC subtypes (HepG2, Hep3B and HuH7) suggested that the disrupted pH homeostasis would amplify the lactate stress to initiate HCC apoptosis, while at the same time also suppressing their migration and invasion abilities. Moreover, safety tests on 7702 cells and living animals revealed that MCT4-blockade treatment has no cytotoxicity against healthy cells/tissues. The results indicate the MCT4-inhibition-induced disruption of tumor intracellular pH holds promise as a therapy against not only HCC, but a broader spectrum of MCT4-overexpressing hyperglycolytic tumors.

Progesterone-induced miR-152 interferes with embryonic implantation by downregulating GLUT3 in endometrial epithelium.

To investigate the role of progesterone-induced micro-RNA (miR)-152 in early embryonic development and implantation by regulating GLUT3 in endometrial epithelium, qRT-PCR was used to detect the expression of miR-152, GLUT1, and GLUT3 in the endometrial epithelial cells of female mice. GLUT1 and GLUT3 proteins were detected by immunohistochemical staining in the mouse endometrial epithelium. Bioinformatics prediction associated with a luciferase assay was performed to determine whether GLUT1 and GLUT3 are target genes of miR-152. Specific miR-152 mimics or inhibitors were transfected into the endometrial epithelial cells to, respectively, overexpress or downregulate miR-152. Next, the glucose concentration of uterine fluid was measured by conducting high-performance liquid chromatography in vivo, and the glucose uptake of the endometrial epithelial cells was observed using a fluorometric assay in vitro. Early embryonic development and implantation were also observed after the miR-152 mimics or inhibitors had been transfected. Embryo transfer was observed after the miR-152 mimic transfection. miR-152 was found to directly target and thereby downregulate GLUT3 expression. The expressions of both miR-152 and GLUT3 in the mouse endometrial epithelium had spatiotemporal characteristics on days 1-4 of pregnancy. miR-152 affected the glucose concentration of uterine fluid and the glucose uptake of endometrial epithelial cells. The transfection of specific miR-152 mimics led to impaired embryonic development and implantation. To conclude, in endometrial epithelial cells, progesterone-induced miR-152 downregulates GLUT3 at the posttranscriptional level to maintain a proper glucose concentration in the uterine fluid, which is necessary for early embryonic development and implantation.

Longitudinal in vivo tracking of adverse effects following topical steroid treatment.

Topical steroids are known for their anti-inflammatory properties and are commonly prescribed to treat many adverse skin conditions such as eczema and psoriasis. While these treatments are known to be effective, adverse effects including skin atrophy are common. In this study, the progression of these effects is investigated in an in vivo mouse model using multimodal optical microscopy. Utilizing a system capable of performing two-photon excitation fluorescence microscopy (TPEF) of reduced nicotinamide adenine dinucleotide (NADH) to visualize the epidermal cell layers and second harmonic generation (SHG) microscopy to identify collagen in the dermis, these processes can be studied at the cellular level. Fluorescence lifetime imaging microscopy (FLIM) is also utilized to image intracellular NADH levels to obtain molecular information regarding metabolic activity following steroid treatment. In this study, fluticasone propionate (FP)-treated, mometasone furoate (MF)-treated and untreated animals were imaged longitudinally using a custom-built multimodal optical microscope. Prolonged steroid treatment over the course of 21 days is shown to result in a significant increase in mean fluorescence lifetime of NADH, suggesting a faster rate of maturation of epidermal keratinocytes. Alterations to collagen organization and the structural microenvironment are also observed. These results give insight into the structural and biochemical processes of skin atrophy associated with prolonged steroid treatment.

Suppressing Short-term Polarization Noise and Related Spectral Decoherence in All-normal Dispersion Fiber Supercontinuum Generation.

The supercontinuum generated exclusively in the normal dispersion regime of a nonlinear fiber is widely believed to possess low optical noise and high spectral coherence. The recent development of flattened all-normal dispersion fibers has been motivated by this belief to construct a general-purpose broadband coherent optical source. Somewhat surprisingly, we identify a large short-term polarization noise in this type of supercontinuum generation that has been masked by the total-intensity measurement in the past, but can be easily detected by filtering the supercontinuum with a linear polarizer. Fortunately, this hidden intrinsic noise and the accompanied spectral decoherence can be effectively suppressed by using a polarization-maintaining all-normal dispersion fiber. A polarization-maintaining coherent supercontinuum laser is thus built with a broad bandwidth (780-1300 nm) and high spectral power (~1 mW/nm).

Coherent phase control of internal conversion in pyrazine.

Shaped ultrafast laser pulses were used to study and control the ionization dynamics of electronically excited pyrazine in a pump and probe experiment. For pump pulses created without feedback from the product signal, the ion growth curve (the parent ion signal as a function of pump/probe delay) was described quantitatively by the classical rate equations for internal conversion of the S2 and S1 states. Very different, non-classical behavior was observed when a genetic algorithm (GA) employing phase-only modulation was used to minimize the ion signal at some pre-determined target time, T. Two qualitatively different control mechanisms were identified for early (T < 1.5 ps) and late (T > 1.5 ps) target times. In the former case, the ion signal was largely suppressed for t < T, while for t ≫ T, the ion signal produced by the GA-optimized pulse and a transform limited (TL) pulse coalesced. In contrast, for T > 1.5 ps, the ion growth curve followed the classical rate equations for t < T, while for t ≫ T, the quantum yield for the GA-optimized pulse was much smaller than for a TL pulse. We interpret the first type of behavior as an indication that the wave packet produced by the pump laser is localized in a region of the S2 potential energy surface where the vertical ionization energy exceeds the probe photon energy, whereas the second type of behavior may be described by a reduced absorption cross section for S0 → S2 followed by incoherent decay of the excited molecules. Amplitude modulation observed in the spectrum of the shaped pulse may have contributed to the control mechanism, although this possibility is mitigated by the very small focal volume of the probe laser.

Noise characterization of broadband fiber Cherenkov radiation as a visible-wavelength source for optical coherence tomography and two-photon fluorescence microscopy.

Optical sources in the visible region immediately adjacent to the near-infrared biological optical window are preferred in imaging techniques such as spectroscopic optical coherence tomography of endogenous absorptive molecules and two-photon fluorescence microscopy of intrinsic fluorophores. However, existing sources based on fiber supercontinuum generation are known to have high relative intensity noise and low spectral coherence, which may degrade imaging performance. Here we compare the optical noise and pulse compressibility of three high-power fiber Cherenkov radiation sources developed recently, and evaluate their potential to replace the existing supercontinuum sources in these imaging techniques.

Optical parametrically gated microscopy in scattering media.

High-resolution imaging in turbid media has been limited by the intrinsic compromise between the gating efficiency (removal of multiply-scattered light background) and signal strength in the existing optical gating techniques. This leads to shallow depths due to the weak ballistic signal, and/or degraded resolution due to the strong multiply-scattering background--the well-known trade-off between resolution and imaging depth in scattering samples. In this work, we employ a nonlinear optics based optical parametric amplifier (OPA) to address this challenge. We demonstrate that both the imaging depth and the spatial resolution in turbid media can be enhanced simultaneously by the OPA, which provides a high level of signal gain as well as an inherent nonlinear optical gate. This technology shifts the nonlinear interaction to an optical crystal placed in the detection arm (image plane), rather than in the sample, which can be used to exploit the benefits given by the high-order parametric process and the use of an intense laser field. The coherent process makes the OPA potentially useful as a general-purpose optical amplifier applicable to a wide range of optical imaging techniques.

Microfluidic-based preparation of artificial antigen-presenting gel droplets for integrated and minimalistic adoptive cell therapy strategies.

Adoptive T-cell transfer for cancer therapy is limited by the inefficiency ofin vitroT-cell expansion and the ability ofin vivoT-cells to infiltrate tumors. The construction of multifunctional artificial antigen-presenting cells is a promising but challenging approach to achieve this goal. In this study, a multifunctional artificial antigen-presenting gel droplet (AAPGD) was designed. Its surface provides regulated T-cell receptor (TCR) stimulation and co-stimulation signals and is capable of slow release of mitogenic cytokines and collagen mimetic peptide. The highly uniform AAPGD are generated by a facile method based on standard droplet microfluidic devices. The results of the study indicate that, T-cell proliferatedin vitroutilizing AAPGD have a fast rate and high activity. AAPGD increased the proportion ofin vitroproliferating T cells low differentiation and specificity. The starting number of AAPGDs and the quality ratio of TCR-stimulated and co-stimulated signals on the surface have a large impact on the rapid proliferation of low-differentiated T cellsin vitro. During reinfusion therapy, AAPGD also enhanced T-cell infiltration into the tumor site. In experiments using AAPGD for adoptive T cell therapy in melanoma mice, tumor growth was inhibited, eliciting a potent cytotoxic T-lymphocyte immune response and improving mouse survival. In conclusion, AAPGD promotes rapid low-differentiation proliferation of T cellsin vitroand enhances T cell infiltration of tumorsin vivo. It simplifies the preparation steps of adoptive cell therapy, improves the therapeutic effect, and provides a new pathway for overdosing T cells to treat solid tumors.

Nanointegrative Glycoengineering-Activated Necroptosis of Triple Negative Breast Cancer Stem Cells Enables Self-Amplifiable Immunotherapy for Systemic Tumor Rejection.

Triple-negative breast cancer stem cells (TCSCs) are considered as the origin of recurrence and relapse. It is difficult to kill not only for its resistance, but also the lacking of targetable molecules on membrane. Here, it is confirmed that ST6 ß-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-1) is highly expressed in TCSCs that may be the key enzyme involved in glycoengineering via sialic acid (SA) metabolism. SA co-localizes with a microdomain on cell membrane termed as lipid rafts that enrich CSCs marker and necroptosis proteins mixed lineage kinase domain-like protein (MLKL), suggesting that TCSCs may be sensitive to necroptosis. Thus, the triacetylated N-azidoacetyl-d-mannosamine (Ac3ManNAz) is synthesized as the glycoengineering substrate and applied to introduce artificial azido receptors, dibenzocyclooctyne (DBCO)-modified liposome is used to deliver Compound 6i (C6), a receptor-interacting serine/threonine protein kinase 1(RIPL1)-RIP3K-mixed lineage kinase domain-like protein(MLKL) activator, to induce necroptosis. The pro-necroptosis effect is aggravated by nitric oxide (NO), which is released from NO-depot of cholesterol-NO integrated in DBCO-PEG-liposome@NO/C6 (DLip@NO/C6). Together with the immunogenicity of necroptosis that releases high mobility group box 1(HMGB1) of damage-associated molecular patterns, TCSCs are significantly killed in vitro and in vivo. The results suggest a promising strategy to improve the therapeutic effect on the non-targetable TCSCs with high expression of ST6Gal-1 via combination of glycoengineering and necroptosis induction.

Broadband nonlinear vibrational spectroscopy by shaping a coherent fiber supercontinuum.

Vibrational spectroscopy has been widely applied in different fields due to its label-free chemical-sensing capability. Coherent anti-Stokes Raman scattering (CARS) provides stronger signal and faster acquisition than spontaneous Raman scattering, making it especially suitable for molecular imaging. Coherently-controlled single-beam CARS simplifies the conventional multi-beam setup, but the vibrational bandwidth and non-trivial spectrum retrieval have been limiting factors. In this work, a coherent supercontinuum generated in an all-normal-dispersion nonlinear fiber is phase-shaped within a narrow bandwidth for broadband vibrational spectroscopy. The Raman spectra can be directly retrieved from the CARS measurements, covering the fingerprint regime up to 1750 cm(-1). The retrieved spectra of several chemical species agree with their spontaneous Raman data. The compact fiber supercontinuum source offers broad vibrational bandwidth with high stability and sufficient power, showing the potential for spectroscopic imaging in a wide range of applications.

Perspectives for Using CO2 as a Feedstock for Biomanufacturing of Fuels and Chemicals.

Microbial cell factories offer an eco-friendly alternative for transforming raw materials into commercially valuable products because of their reduced carbon impact compared to conventional industrial procedures. These systems often depend on lignocellulosic feedstocks, mainly pentose and hexose sugars. One major hurdle when utilizing these sugars, especially glucose, is balancing carbon allocation to satisfy energy, cofactor, and other essential component needs for cellular proliferation while maintaining a robust yield. Nearly half or more of this carbon is inevitably lost as CO2 during the biosynthesis of regular metabolic necessities. This loss lowers the production yield and compromises the benefit of reducing greenhouse gas emissions-a fundamental advantage of biomanufacturing. This review paper posits the perspectives of using CO2 from the atmosphere, industrial wastes, or the exhausted gases generated in microbial fermentation as a feedstock for biomanufacturing. Achieving the carbon-neutral or -negative goals is addressed under two main strategies. The one-step strategy uses novel metabolic pathway design and engineering approaches to directly fix the CO2 toward the synthesis of the desired products. Due to the limitation of the yield and efficiency in one-step fixation, the two-step strategy aims to integrate firstly the electrochemical conversion of the exhausted CO2 into C1/C2 products such as formate, methanol, acetate, and ethanol, and a second fermentation process to utilize the CO2-derived C1/C2 chemicals or co-utilize C5/C6 sugars and C1/C2 chemicals for product formation. The potential and challenges of using CO2 as a feedstock for future biomanufacturing of fuels and chemicals are also discussed.

Coordination-driven FBXW7 DNAzyme-Fe nanoassembly enables a binary switch of breast cancer cell cycle checkpoint responses for enhanced ferroptosis-radiotherapy.

Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe2+-mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. STATEMENT OF SIGNIFICANCE: To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair, eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.

Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells.

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

High Sensitivity Singlet Oxygen Luminescence Sensor Using Computational Spectroscopy and Solid-State Detector.

This paper presents a technique for high sensitivity measurement of singlet oxygen luminescence generated during photodynamic therapy (PDT) and ultraviolet (UV) irradiation on skin. The high measurement sensitivity is achieved by using a computational spectroscopy (CS) approach that provides improved photon detection efficiency compared to spectral filtering methodology. A solid-state InGaAs photodiode is used as the CS detector, which significantly reduces system cost and improves robustness compared to photomultiplier tubes. The spectral resolution enables high-accuracy determination and subtraction of photosensitizer fluorescence baseline without the need for time-gating. This allows for high sensitivity detection of singlet oxygen luminescence emission generated by continuous wave light sources, such as solar simulator sources and those commonly used in PDT clinics. The value of the technology is demonstrated during in vivo and ex vivo experiments that show the correlation of measured singlet oxygen with PDT treatment efficacy and the illumination intensity on the skin. These results demonstrate the potential use of the technology as a dosimeter to guide PDT treatment and as an analytical tool supporting the development of improved sunscreen products for skin cancer prevention.

YTHDF1 upregulation mediates hypoxia-dependent breast cancer growth and metastasis through regulating PKM2 to affect glycolysis.

N6-methyladenosine modification is the most common RNA modification mechanism in mammals. YTHDF1, a m6A reader, can recognize the m6A of mRNAs to facilitate the interaction with the mRNA ribosome assembly and recruitment of translation initiators to promote translation. From a clinical perspective, YTHDF1 upregulation is frequently observed in breast cancer, but its involvement in those cancer-related events is still unclear. Here we report that YTHDF1 is a cancer driver capable of facilitating the proliferation and invasion of breast cancer cells as well as enhancing tumorigenicity and metastasis through promoting glycolysis. We found that tumor hypoxia can transcriptionally induce HIF1α and post-transcriptionally inhibit the expression of miR-16-5p to promote YTHDF1 expression, which could sequentially enhance tumor glycolysis by upregulating PKM2 and eventually increase the tumorigenesis and metastasis potential of breast cancer cells. Inhibiting YTHDF1 via gene knockdown or miR-16-5p would significantly abolish YTHDF1-dependent tumor growth and metastasis. In summary, we identified the role of the YTHDF1-PKM2 signal axis in the occurrence and development of breast cancer, which can be used as a potential target for breast cancer treatment.

An ROS-Activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.

Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy is developed. First ferrocene is conjugated on PEGylated polyamidoamine dendrimers via reactive oxygen species (ROS)-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies can be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterward DEM can directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense, while siMCT4 can block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which can improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrates high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability.