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The development of vitrimers, dynamic covalent bonds cross-liked polymers via the associative exchange mechanism, offers a feasible way to address the recycling issue of traditional chemically cross-linked polyethylene (PE). However, it is still a great challenge to simultaneously achieve recyclability and high performance through a route that is environmentally friendly and easy to scale up. In this work, low-density (LD) PE vitrimers cross-linked by β-hydroxy ester bonds were successfully obtained via reactive processing between polyethylene-co-glycidyl methacrylate (PE-GMA) and decanedioic acid (DA). The high reaction efficiency of epoxy and carboxy groups leads to a high gel content of 84.51%. The activation energy (Ea) of the transesterification reaction is calculated to be 111.33 kJ·mol–1. Thanks to the high Eaand cross-link density, the obtained (LD) PE vitrimer exhibits a superior tensile strength of 20.41 MPa and an elongation at break of 800.16%, which is one of the highest values among the currently reported PE vitrimers fabricated by reactive processing. Moreover, the (LD) PE vitrimers have good creep resistance, heat resistance, and electrical insulation, thus showing a great potential to be used in the field of cable insulation.

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 β‐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. PLip@Ac3M incorporates azido receptors on TCSCs surface through ST6Gal‐1‐dependent sialic acid (SA) metabolism routes, which are recognized and targeted via bioorthogonal click reactions with DLip@NO/C6 to deliver C6 and NO, thus inducing effective necroptosis‐immunotherapy for TCSC elimination.

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.

Cancer stem cells (CSCs) are promising targets for improving anticancer treatment outcomes while eliminating recurrence, but their treatment remains a major challenge. Here, we report a nanointegrative strategy to realize CSC-targeted ferroptosis-immunotherapy through spatiotemporally controlled reprogramming of STAT3-regulated signaling circuits. Specifically, STAT3 inhibitor niclosamide (Ni) and an experimental ferroptosis drug (1S, 3R)-RSL3 (RSL3) are integrated into hyaluronic acid-modified amorphous calcium phosphate (ACP) nanounits through biomineralization (CaP-PEG-HA@Ni/RSL3), which could be recognized by CD44-overexpressing CSCs and released in a synchronized manner. Ni inhibits the CSC-intrinsic STAT3-PD-L1 axis to stimulate adaptive immunity and enhance interferon gamma (IFNγ) secretion by CD8+T cells to downregulate SLC7A11 and SLC3A2 for blocking glutathione biosynthesis. Meanwhile, Ni-dependent STAT3 inhibition also upregulates ACSL4 through downstream signaling and IFNγ feedback. These effects cooperate with RSL3-mediated GPX4 deactivation to induce pronounced ferroptosis. Furthermore, CaP-PEG-HA@Ni/RSL3 also impairs the immunosuppressive M2-like tumor-associated macrophages, while Ca2+ions released from degraded ACP could chelate with lipid peroxides in ferroptotic CSCs to avoid CD8+T-cell inhibition, thus boosting the effector function of activated CD8+T cells. This study offers a cooperative ferroptosis-immunotherapeutic approach for the treatment of refractory cancer.

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.

The platform described here combines the non-invasive measurement of the retina/choroid structure and ocular blood flow based on optical coherence tomography (OCT) and wide-field semi-quantitative global flow visualization using line-scanning Doppler flowmetry (LSDF). The combination of these two imaging modalities within the same platform enables comprehensive assessment of blood flow in the retina and choroid in animals and human subjects for diagnostic purposes. Ultra-widefield vasculature visualization is demonstrated here for the first time without injecting additional contrast agents and based only on the motion of particles within the vasculature.

Retinal-based opsins are light-sensitive proteins. The photoisomerization reaction of these proteins has been studied outside cellular environments using ultrashort tailored light pulses. However, how living cell functions can be modulated via opsins by modifying fundamental nonlinear optical properties of light interacting with the retinal chromophore has remained largely unexplored. We report the use of chirped ultrashort near-infrared pulses to modulate light-evoked ionic current from Channelrhodopsin-2 (ChR2) in brain tissue, and consequently the firing pattern of neurons, by manipulating the phase of the spectral components of the light. These results confirm that quantum coherence of the retinal-based protein system, even in a living neuron, can influence its current output, and open up the possibilities of using designer-tailored pulses for controlling molecular dynamics of opsins in living tissue to selectively enhance or suppress neuronal function for adaptive feedback-loop applications in the future.

The healing process is often significantly impaired under conditions of chronic or large area wounds, which are often treated clinically using autologous split-thickness skin grafts. However, in many cases, harvesting of donor tissue presents a serious problem such as in the case of very large area burns. In response to this, engineered biomaterials have emerged that attempt to mimic the natural skin environment or deliver a suitable therapy to assist in the healing process. In this study, a custom-built multimodal optical microscope capable of noninvasive structural and functional imaging is used to investigate both the engineered tissue microenvironment and the in vivowound healing process. Investigation of various engineered scaffolds show the strong relationship among the microenvironment of the scaffold, the organization of the cells within the scaffold, and the delivery pattern of these cells onto the healing wound. Through noninvasive tracking of these processes and parameters, multimodal optical microscopy provides an important tool in the assessment of engineered scaffolds both in vitroand in vivo.

Tumor microenvironment (TME) plays decisive roles in debilitating 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. Herein, we report that stiffened ECM contributes to the immunosuppressive TME via activating ROCK-myosin IIA-F-actin mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging NMHC-IIA-F-actin stress fibers, thus accelerating the autophagic degradation of cGAS to deprive tumor cGAMP and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with Blebbistatin (BELB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) both 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 ROCK-myosin IIA-F-actin axis, while inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

The preparation, staining, visualization and interpretation of histological images of tissue is well accepted as the gold standard process for the diagnosis of disease. These methods have a long history of development, and are used ubiquitously in pathology, despite being highly time- and labour-intensive. Here, we introduce a unique optical imaging platform and methodology for label-free multimodal multiphoton microscopy that uses a novel photonic-crystal fibre source to generate tailored chemical contrast based on programmable supercontinuum pulses. We demonstrate the collection of optical signatures of the tumour microenvironment, including evidence of mesoscopic biological organization, tumour cell migration and (lymph-) angiogenesis collected directly from fresh ex vivomammary tissue. Acquisition of these optical signatures and other cellular or extracellular features, which are largely absent from histologically processed and stained tissue, combined with an adaptable platform for optical alignment-free programmable-contrast imaging, offers the potential to translate stain-free molecular histopathology into routine clinical use.

We demonstrate real-time, longitudinal, label-free tracking of apoptotic and necrotic cells in living tissue using a multimodal microscope. The integrated imaging platform combines multi-photon microscopy (MPM, based on two-photon excitation fluorescence), optical coherence microscopy (OCM), and fluorescence lifetime imaging microscopy (FLIM). Three-dimensional (3-D) co-registered images are captured that carry comprehensive information of the sample, including structural, molecular, and metabolic properties, based on light scattering, autofluorescence intensity, and autofluorescence lifetime, respectively. Different cell death processes, namely, apoptosis and necrosis, of keratinocytes from different epidermal layers are longitudinally monitored and investigated. Differentiation of the two cell death processes in a complex living tissue environment is enabled by quantitative image analysis and high-confidence classification processing based on the multidimensional, cross-validating imaging data. These results suggest that despite the limitations of each individual label-free modality, this multimodal imaging approach holds the promise for studies of different cell death processes in living tissue and in vivo organs.

We describe a versatile, catheter-type two-photon probe, designed for in vivo and ex vivo imaging of the aqueous outflow pathway in the eye. The device consists of a silica double cladding fiber used for laser delivery and fluorescence collection, a spiral fiber scanner driven by a miniature piezoelectric tube, and an assembly of three micro-size doublet achromatic lenses used for focusing the laser and collecting the two-photon excitation signal. All the components have a maximum diameter of 2 mm and are enclosed in a length of 12-gauge stainless steel hypodermic tubing having an outer diameter of 2.8 mm. The lateral and axial resolutions of the probe are measured to be 1.5 μm and 9.2 μm, respectively. Different lens configurations and fibers are evaluated by comparing their spatial resolutions and fluorescence signal collection efficiencies. Doublet achromatic lenses and a double cladding fiber with a high inner cladding numerical aperture are found to produce a high signal collection efficiency, which is essential for imaging live tissues. Simple methods for reducing image distortions are demonstrated. Images of human trabecular meshwork tissue are successfully obtained with this miniature two-photon microscope.

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. Ferroptosis is an emerging paradigm in antitumor treatment, but its efficacy is impeded by the reinforced antioxidant system and alkiline cytosolic pH of tumor cells. Here, a nanointegrated strategy consisting of clinically‐safe components to sensitize tumor cells for ferroptosis treatment, which is realized through the cooperative regulation of glutathione and lactic acid metabolism, is reported.

We analyze theoretically the dispersion of linearly polarized light propagating in a uniaxial anisotropic medium where multibeam interference is present. Explicit expressions of the group-delay dispersion for transmitting waves are derived for the simplest situation, and the effect of dispersion on pulse broadening is analyzed for a few selected cases. Our results reveal that at normal incidence and in the situation where the optic axis is parallel to the surface of birefringent plate (in the x–y plane), the dispersion of the refracted wave decreases with the extent of birefringence. In particular, the dispersion for the electric field parallel to the polarization direction of the incident light changes with the rotation angle between the optic axis and the polarization direction of the incident field, whereas the dispersion for the refracted field whose direction is vertical to the polarization of incident light is independent of this angle. For oblique incidence, dispersion varies substantially for different incident angles. In the situation where the optic axis is in the x–z plane at either normal or oblique incidence, the dispersion increases in a periodically oscillating manner as a function of the relative thickness of the birefringent plate.

In this short communication, we report a novel route to control the selective distribution of hydrophilic silica (SiO2) in polylactide/ethylene-co-vinyl-acetate (PLA/EVA) blends via tailoring the OH surface concentration of silica (often expressed as silanol number). Interestingly, SiO2nanoparticles with low silanol number are mainly distributed in the EVA phase; those with medium silanol number are evenly dispersed in the EVA phase and between PLA and EVA phase; while those with high silanol number are primarily accumulated at the phase interface in the form of large agglomerates. The silanol number induced dispersion and distribution of SiO2could be due to the regulated interactions between SiO2, EVA and PLA. Furthermore, the introduction of uniformly interfacial localized SiO2imparts the blends a significantly improved impact toughness and well maintained strength and modulus. This work demonstrates that tuning the silanol number is a universal platform to manipulate the selective distribution of SiO2toward a good stiffness-toughness balance in SiO2filled immiscible polymer blends.

Ferroptosis is a recently discovered form of programed cell death caused by the metabolically regulated lipid peroxidation and holds promise for cancer treatment, but its regulatory mechanisms remain elusive. In this study, we observe that lactate-rich liver cancer cells exhibit enhanced resistance to the ferroptotic damage induced by common ferroptosis inducers such as Ras-selective lethal small molecule 3 (RSL3) and Erastin and that the monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids. Additionally, blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility. In vitroand in vivoevidence confirms that lactate regulates the ferroptosis of HCC cells and highlights its translational potential as a therapeutic target for ferroptosis-based tumor treatment.

It is shown that plasma polarization measurements can be used to enhance the sensitivity of laser-induced breakdown spectroscopy (LIBS). The polarization of the plasma emission is used to suppress the continuum with only slight attenuation of the discrete atomic and ionic spectra. The method is demonstrated for LIBS detection of copper and carbon samples ablated by pairs of femtosecond laser pulses.