The Tumor Microenvironment: Signal Transduction.

In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.

Hierarchical self-recognition and response in CSC and non-CSC micro-niches for cancer therapy.

Cancer stem cells (CSCs) characterized by self-renewal, invasiveness, tumorigenicity and resistance to treatment are regarded as the thorniest issues in refractory tumors. We develop a targeted and hierarchical controlled release nano-therapeutic platform (SEED-NPs) that self-identifies and responds to CSC and non-CSC micro-niches of tumors. In non-CSC micro-niche, reactive oxygen species (ROS) trigger the burst release of the chemotherapeutic drug and photosensitizer to kill tumor cells and reduce tumor volume by combining chemotherapy and photodynamic therapy (PDT). In CSC micro-niche, the preferentially released differentiation drug induces CSC differentiation and transforms CSCs into chemotherapy-sensitive cells. SEED-NPs exhibit an extraordinary capacity for downregulating the stemness of CD44+/CD24- SP (side population) cell population both in vitro and in vivo, and reveal a 4-fold increase of tumor-targeted accumulation. Also, PDT-generated ROS promote the formation of tunneling nanotubes and facilitate the divergent network transport of drugs in deep tumors. Moreover, ROS in turn promotes CSC differentiation and drug release. This positive-feedback-loop strategy enhances the elimination of refractory CSCs. As a result, SEED-NPs achieve excellent therapeutic effects in both 4T1 SP tumor-bearing mice and regular 4T1 tumor-bearing mice without obvious toxicities and eradicate half of mice tumors. SEED-NPs integrate differentiation, chemotherapy and PDT, which proved feasible and valuable, indicating that active targeting and hierarchical release are necessary to enhance antitumor efficacy. These findings provide promising prospects for overcoming barriers in the treatment of CSCs.

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy.

Cancer progression and treatment-associated cellular stress impairs therapeutic outcome by inducing resistance. Endoplasmic reticulum (ER) stress is responsible for core events. Aberrant activation of stress sensors and their downstream components to disrupt homeostasis have emerged as vital regulators of tumor progression as well as response to cancer therapy. Here, an orchestrated nanophotoinducer (ERsNP) results in specific tumor ER-homing, induces hyperthermia and mounting oxidative stress associated reactive oxygen species (ROS), and provokes intense and lethal ER stress upon near-infrared laser irradiation. The strengthened "dying" of ER stress and ROS subsequently induce apoptosis for both primary and abscopal B16F10 and GL261 tumors, and promote damage-associated molecular patterns to evoke stress-dependent immunogenic cell death effects and release "self-antigens". Thus, there is a cascade to activate maturation of dendritic cells, reprogram myeloid-derived suppressor cells to manipulate immunosuppression, and recruit cytotoxic T lymphocytes and effective antitumor response. The long-term protection against tumor recurrence is realized through cascaded combinatorial preoperative and postoperative photoimmunotherapy including the chemokine (C-C motif) receptor 2 antagonist, ERsNP upon laser irradiation, and an immune checkpoint inhibitor. The results highlight great promise of the orchestrated nanophotoinducer to exert potent immunogenic cell stress and death by reinforcing ER stress and oxidative stress to boost cancer photoimmunotherapy.

Small-Molecule Copper Chloride Modulating the Buried Interfaces of Perovskite Solar Cells.

In perovskite solar cells (PSCs), tin dioxide (SnO2) is a highly effective electron transport material. On the other hand, the low intrinsic conductivity of SnO2, the high trap-state density on the surface and bulk of SnO2, and inadequate interface contacts between SnO2 and perovskite significantly impact device performance. Herein, small-molecule copper(II) chloride (CuCl2) is introduced into the SnO2 dispersion, which inhibits the agglomeration of SnO2 colloids and improves the quality of the electron transport layer. Furthermore, the introduction of CuCl2 optimizes the energy-level array between the ETL and perovskite layer (PVK) and passivates the anion/cation defects in SnO2, perovskite, and their interface, realizing the systematic modulation of the photoelectronic properties of the ETLs and PVKs as well as the PVK/ETL. As a result, the CuCl2-opmized PSC exhibits an impressive power conversion efficiency of 23.71%, along with improved stability.

Poly(3-hexylthiophene)/perovskite Heterointerface by Spinodal Decomposition Enabling Efficient and Stable Perovskite Solar Cells.

The best research-cell efficiency of perovskite solar cells (PSCs) is comparable with that of mature silicon solar cells (SSCs); However, the industrial development of PSCs lags far behind SSCs. PSC is a multiphase and multicomponent system, whose consequent interfacial energy loss and carrier loss seriously affect the performance and stability of devices. Here, by using spinodal decomposition, a spontaneous solid phase segregation process, in situ introduces a poly(3-hexylthiophene)/perovskite (P3HT/PVK) heterointerface with interpenetrating structure in PSCs. The P3HT/PVK heterointerface tunes the energy alignment, thereby reducing the energy loss at the interface; The P3HT/PVK interpenetrating structure bridges a transport channel, thus decreasing the carrier loss at the interface. The simultaneous mitigation of energy and carrier losses by P3HT/PVK heterointerface enables n-i-p geometry device a power conversion efficiency of 24.53% (certified 23.94%) and excellent stability. These findings demonstrate an ingenious strategy to optimize the performance of PSCs by heterointerface via Spinodal decomposition.

Potassium cobalt hexacyanoferrate as a peroxidase mimic for electrochemical immunosensing of Lactobacillus rhamnosus GG.

In this paper, the potassium cobalt hexacyanoferrate (II), K2CoFe(CN)6, with peroxidase-like activity was used for the fabrication of a novel label-free Lactobacillus rhamnosus GG (LGG) electrochemical immunosensor. The K2CoFe(CN)6 nanocubes were made by a simple hydrothermal method and followed by low-temperature calcination. In addition to structural characterization, the peroxidase-mimicking catalytic property of the material was confirmed by a chromogenic reaction. It is known that H2O2 can oxidize electroactive thionine molecules under the catalysis of horseradish peroxidase (HRP). In this nanozyme-based electrochemical immunoassay, due to the steric hindrance, the formation of immune-complex of LGG and LGG antibody on the modified GCE inhibits the catalytic activity of the peroxidase mimics of K2CoFe(CN)6 and thus reduced the current signal. Therefore, the developed electrochemical immunosensor achieved quantitative detection of LGG. Under optimal conditions, the linear range of the sensor was obtained from 101 to 106 CFU mL-1 with a minimum detection limit (LOD) of 12 CFU mL-1. Furthermore, the immunosensor was successfully applied in the quantitative detection of LGG in dairy product samples with recoveries ranging from 93.2% to 106.8%. This protocol presents a novel immunoassay method, which provides an alternative implementation pathway for the quantitative detection of microorganisms.

Revealing the Enhanced Thermoelectric Properties of Controllably Doped Donor-Acceptor Copolymer: The Impact of Regioregularity.

Albeit considerable attention to the fast-developing organic thermoelectric (OTE) materials due to their flexibility and non-toxic features, it is still challenging to design an OTE polymer with superior thermoelectric properties. In this work, two "isomorphic" donor-acceptor (D-A) conjugated polymers are studied as the semiconductor in OTE devices, revealing for the first time the internal mechanism of regioregularity on thermoelectric performances in D-A type polymers. A higher molecular structure regularity can lead to higher crystalline order and mobility, higher doping efficiency, order of energy state, and thermoelectric (TE) performance. As a result, the regioregular P2F exhibits a maximum power factor (PF) of up to 113.27 µW m-1  K-2 , more than three times that of the regiorandom PRF (35.35 µW m-1  K-2 ). However, the regular backbone also implies lower miscibility with a dopant, negatively affecting TE performance. Therefore, the trade-off between doping efficiency and miscibility plays a vital role in OTE materials, and this work sheds light on the molecular design strategy of OTE polymers with state-of-the-art performances.

An ultrasensitive bacterial imprinted electrochemical sensor for the determination of Lactobacillus rhamnosus GG.

An ultrasensitive label-free electrochemical sensor based on a homemade imprinted polypyrrole (PPy) polymer film was prepared to achieve quantitative determination of Lactobacillus rhamnosus GG (LGG). The LGG-imprinted polymer (LIP) film was deposited on a portable screen-printed electrode (SPE) via electropolymerization, which constituted an independent integrated system. The main preparation parameters of the LIP sensor were investigated to obtain optimal performance. Under optimized conditions, the peak current response of the LIP sensor showed a linear relationship with the logarithmic value of LGG concentration in the range from 101 to 109 CFU mL-1 and a detection limit of 5 CFU mL-1. The proposed LIP sensor has achieved efficient, ultrasensitive, highly selective, and cost-effective detection of LGG and can be further developed for practical applications in the quality inspection and development of probiotic products.

Symmetry-Breaking Induced Dipole Enhancement for Efficient Spiro-Type Hole Transporting Materials: Easy Synthesis with High Stability.

Spiral cores are crucial for designing efficient hole transporting materials (HTMs) for perovskite solar cells (PSCs), owing to their no-planar 3D architecture, high thermal stability, good solubility, and beneficial solid-state morphology. A lack of facile synthetic procedures for the spiral core limited the development of novel and stable spiral HTMs. In this regard, a one-step reaction is adopted to produce several novel acceptor-embedded spiral cores containing electron-withdrawing carbonyl group embedded orthogonal spiral conformation. After coupling with triphenylamine donors, symmetry-breaking spiral HTMs with uneven charge distribution can be obtained, bearing the advantages of adjustable dipole moment and enhanced structural stability. A combined theoretical and experimental study shows that the HTM with a stronger dipole moment can easily adsorb on the surface of perovskite via electrostatic potential, and the closer distance promoted facile hole transfer from perovskite to HTMs. In the end, PSCs based on strongly polarized spiro-BC-OMe achieved efficient hole extraction and thus an improved fill factor, promoting a power conversion efficiency (PCE) of 22.15%, and a module-based PCE of 18.61% with an active area of 16.38 cm2 . This study provides a new avenue for designing HTMs with strong dipole moments for efficient PSCs.

Dendritic cell derived exosomes loaded neoantigens for personalized cancer immunotherapies.

Despite the promising potential of cancer vaccine, their efficacy has been limited in clinical trials and improved methods are urgently needed. Here we designed a nanovaccine platform that contains dendritic cell derived exosomes carriers and patient-specific neoantigens for individualized immunotherapies. The nanovaccine exhibited convenient cargo loading and prolonged cargo transportation to the lymph nodes, followed by eliciting potent antigen specific broad-spectrum T-cell and B-cell-mediated immune responses with great biosafety and biocompatibility. Strikingly, delivery of neoantigen-exosome nanovaccine significantly prohibited tumor growth, prolonged survival, delayed tumor occurrences with long-term memory, eliminated the lung metastasis in the therapeutic, prophylactic and metastatic B16F10 melanoma as well as therapeutic MC-38 models, respectively. Additionally, exosome-based nanovaccine demonstrated synergistic antitumor response superior to liposomal formulation due to presence of exosomal proteins. Collectively, our research indicated improved strategies for cell free vaccines and suggested exosome-based nanoplatform for cancer immunotherapy and personalized nanotechnology. These findings represent a powerful pathway to generate individualized nanovaccine rapidly for clinical application.

Polarized Molecule 4-(Aminomethyl) Benzonitrile Hydrochloride for Efficient and Stable Perovskite Solar Cells.

The rapid development of perovskite solar cells (PSCs) makes it one of the most competitive photovoltaic devices in the field of new energy. However, the suboptimal performance and poor stability caused by numerous defects are still the main factors limiting the development of PSCs. Herein, a polarized molecule additive of 4-(aminomethyl) benzonitrile hydrochloride (AMBNCl) is introduced into perovskite. Owing to its special polar electron density distribution, -C≡N group, -NH3+ terminal, and Cl- ions, the modification of AMBNCl can improve the quality of perovskite crystal growth, passivate the defects of Pb2+, adjust the energy level array between the perovskite layer and hole-transport layer, and alleviate the carrier nonradiative recombination. As a result, the AMBNCl-modified device achieves a champion efficiency of 23.52%. The unpacked device still maintained 91.2% of its original efficiency after storing in an air environment (RH ∼40%, 25 °C) for 50 days.

Bulky ammonium iodide and in-situ formed 2D Ruddlesden-Popper layer enhances the stability and efficiency of perovskite solar cells.

The practical applications of perovskite solar cells (PSCs) are limited by the further improvement of their stability and performance. Interface engineering is a promising strategy to solve these pain points. Herein, we design (R)-(-)-1-cyclohexylethylamine iodide (R-CEAI), composed of positively charged hydrophobic R-CEA+ and negatively charged I-, to post-treat the interface of 3D mixed-cation/halide perovskite with assist one of isopropyl alcohol (IPA). R-CEAI treatment not only passivates the defects at surface and grain boundaries of perovskite, but also in-situ grows quasi 2D Ruddlesden-Popper perovskite at the interface between 3D perovskite and hole transport layer, which reduces trap density of states, tunes energy level and alleviates lattice distortion. As a result, R-CEAI treated 2D/3D PSCs yield a champion PCE of 22.52%, with an improved open-circuit voltage of 1.195 V and retain 84.34% of their initial efficiency in long-term stability test, while the pristine device provides a PCE of 19.43% with only 54.30% retention.

Surface Reconstruction and In Situ Formation of 2D Layer for Efficient and Stable 2D/3D Perovskite Solar Cells.

The 2D/3D composite structure possesses both the excellent stability of 2D perovskite and the excellent performance of 3D perovskite, which recently have attracted special attention. Different from the popular isopropanol, a novel additive solvent-polypropylene glycol bis (2-aminopropyl ether) (A-PPG) is introduced here to dissolve excess PbI2 and perovskite, and then reconstruct and in situ form the quasi-2D perovskite layer on 3D perovskite bulk. The lone electron pairs of the ether-oxygen and amino in A-PPG can form coordination bonds with Pb2+ . The introduction of A-PPG tunes the energy array of functional layers, passivates defects, and mitigates carrier nonradiative recombination. Consequently, the 2D/3D perovskite device exhibits a championship efficiency of 22.24% with a distinguished open-circuit voltage of 1.21 V (the thermodynamic limit of 1.30 V). Moreover, the 2D/3D device still maintains 90% of the original efficiency in the ambient atmosphere with a relative humidity of 30 ± 10% after 50 days.

N, O-codoped hierarchical porous graphitic carbon for electrochemical immunosensing of Lactobacillus rhamnosus GG.

An ultrasensitive label-free electrochemical immunosensor was fabricated for quantitative detection of Lactobacillus rhamnosus GG (LGG). The N/O co-doped three-dimensional hierarchical porous graphitic (THPG) carbon was synthesized by a one-step synthesis of polyaniline hydrogel, and followed by simple carbonization and chemical activation procedures. Because of the unique structure design, the obtained THPG carbon networks possess an ultra-large specific surface area of 4859 m2 g-1 along with a class of highly graphitic carbons. The results offer an enormous surface area and excellent electrical conductivity for label-free electrochemical immunosensing of probiotic L. rhamnosus strain. Under optimal conditions, the immunosensor showed a good linear relationship between peak current and concentration of LGG (R2 = 0.9976), with a detection limit of 2 CFU mL-1. Furthermore, this label-free immunosensor also shows good specificity, long-term stability, and reliability, and could be applied to detect probiotic LGG in dairy products and drinks with satisfactory results. The present protocol was shown to be quite promising for practical screening and functional evaluation of probiotic products containing LGG. A ultrasensitive label-free electrochemical immunosensor based on THPG carbon was fabricated for detection of Lactobacillus rhamnosus GG.

Phthalide and 1-Iodooctadecane Synergistic Optimization for Highly Efficient and Stable Perovskite Solar Cells.

The carrier non-radiative recombination and instability of device caused by the inherent defects are main factors limiting development of perovskite solar cells (PSCs). During the fabrication process of a PSC device, perovskite films often produce Pb0 and I0 defects. This paper reports a strategy for synergistic optimization of perovskite films by defects passivation and surface modification. The doping of phthalide (PT) in the Pb-rich (CH(NH2 )2 )1-x (CH3 NH3 )x PbI3 film can passivate lead cation defects, and the modification of 1-iodooctadecane (1-IO) can reduce halogen anion defects and improve stability of PSCs owing to its hydrophobicity. The PT and 1-IO optimized device achieves a power conversion efficiency (PCE) of 22.27%. The optimized PSCs remain 93.2% of the initial PCE when placed in air environment (relative humidity of 10%, 25 °C) more than 70 days. The PT and 1-IO synergistic optimization provides a novel strategy for improving the performance and stability of PSCs.

Enhanced photovoltage and stability of perovskite photovoltaics enabled by a cyclohexylmethylammonium iodide-based 2D perovskite passivation layer.

Regardless of the impressive progress that perovskite solar cells (PSCs) have achieved, especially considering their power conversion efficiency (PCE) over 25%, traditional PSCs still contend with an inherent instability with exposure to humidity, which remains as a critical issue for the realization of commercial production. Herein, we proposed an effective pathway to relieve the instability of PSCs without sacrificing efficiency by introducing a 2D phase at the surface of the 3D perovskite film, based on a novel organic cyclohexylmethylammonium iodide (CMAI). The self-assembled thin 2D capping layer atop the 3D perovskite layer can not only reduce the ionic defects, but also serve as a protective barrier against moisture. Consequently, the champion device incorporating 2D perovskite capping layers delivered an open-circuit voltage (Voc) of 1.19 V, which contributes to an impressive PCE of 22.06% on account of the improved charge extraction and decreased non-radiative recombination. More importantly, an excellent long-term stability along with mitigated hysteresis was observed for the modified devices as a result of the suppressed ion migration and high humidity resistance of the 2D perovskite film. Our finding provides a comprehensive approach for simultaneously enhancing the efficiency and stability of PSCs through dimension engineering utilizing CMA-based 2D perovskite materials.

Marked Passivation Effect of Naphthalene-1,8-Dicarboximides in High-Performance Perovskite Solar Cells.

As game-changers in the photovoltaic community, perovskite solar cells are making unprecedented progress while still facing grand challenges such as improving lifetime without impairing efficiency. Herein, two structurally alike polyaromatic molecules based on naphthalene-1,8-dicarboximide (NMI) and perylene-3,4-dicarboximide (PMI) with different molecular dipoles are applied to tackle this issue. Contrasting the electronically pull-pull cyanide-substituted PMI (9CN-PMI) with only Lewis-base groups, the push-pull 4-hydroxybiphenyl-substituted NMI (4OH-NMI) with both protonic and Lewis-base groups can provide better chemical passivation for both shallow- and deep-level defects. Moreover, combined theoretical and experimental studies show that the 4OH-NMI can bind more firmly with perovskite and the polyaromatic backbones create benign midgap states in the excited perovskite to suppress the damage by superoxide anions (energetic passivation). The polar and protonic nature of 4OH-NMI facilitates band alignment and regulates the viscosity of the precursor solution for thicker perovskite films with better morphology. Consequently, the 4OH-NMI-passivated perovskite films exhibit reduced grain boundaries and nearly three-times lower defect density, boosting the device efficiency to 23.7%. A more effective design of the passivator for perovskites with multi-passivation mechanisms is provided in this study.

Engineered Microglia Potentiate the Action of Drugs against Glioma Through Extracellular Vesicles and Tunneling Nanotubes.

Gliomas remain difficult to treat because of their metastatic and recurrent nature and the existence of the blood-brain barrier (BBB), which impedes drug delivery. Microglia, the resident macrophages in the CNS, can be recruited by gliomas and can penetrate the tumor. In this study, microglia (BV2 cells) are used as transport vectors to deliver paclitaxel for the treatment of glioma. To avoid paclitaxel toxicity in microglia, liposomes are first employed to isolate the drug from BV2 cells. Dipalmitoyl phosphatidylserine (DPPS), as an "eat me" signal, is doped into liposomes to amplify their phagocytosis by microglia. This study demonstrates that engineered microglia can cross the BBB, independently migrate toward gliomas, and transfer cargo to glioma cells. Of note, extracellular vesicles and tunneling nanotubes are found to offer unique modes of cargo transportation between microglia and glioma cells. In vivo, the engineered drug-loaded microglia has a high ability to target the brain, penetrate glioma, and suppress tumor progression, supporting the notion that the use of engineered microglia is a potential strategy for the treatment of glioma. These findings present new opportunities for exploration into the use of microglia as transport vectors to deliver therapeutic agents through specific membrane nanotubes and vesicles.

Plasmon-Enhanced Perovskite Solar Cells with Efficiency Beyond 21 %: The Asynchronous Synergistic Effect of Water and Gold Nanorods.

Although perovskite films have excellent extinction coefficients, further increase of the light-absorbing capacity by increasing the thickness of the active layer is always required in perovskite solar cells (PSCs). However, to maintain the morphology quality of the perovskite layer, the film thickness is subject to certain restrictions. To increase the light absorbance without significantly inflating the perovskite film while keeping the high quality of the perovskite film, herein, we added an aqueous solution of gold nanorods (AuNRs) to the perovskite precursor solution via a so-called asynchronous synergistic effect (ASE) strategy of water and AuNR. The former improves the quality of the perovskite film during the crystallization process to reduce defect density and enhance carrier mobility. Simultaneously, the latter increases the light absorption of the perovskite layer through the localized surface plasmon resonance (LSPR) effect when the device is exposed to light. We show that the ASE strategy leads to an excellent power conversion efficiency (PCE) of 21.73 % and outstanding long-term stability, which can retain 95 % of its initial PCE after storage for three months in an air atmosphere.

Phototherapy and anti-GITR antibody-based therapy synergistically reinvigorate immunogenic cell death and reject established cancers.

Phototherapy and immunogenic cell death (ICD) are powerful strategies to fight cancer. However, their therapeutic outcomes are diminished by immunosuppressive and hypoxia microenvironment. Herein, a photo-based, immunomodulating and hypoxia-alleviated nanosystem, PDA-ICG@CAT-DTA-1, is proposed to achieve the synergism between phototherapy and immunotherapy. Catalase (CAT) and anti-GITR antibody (DTA-1) are loaded to photothermal agent and photosensitizer composed PDA-ICG nanoparticles. The PDA-ICG@CAT-DTA-1 exhibits intrinsic local hyperthermia and enhanced ROS generation in tumor, and abrogates tumor immune suppression. It results in reduction of intratumoral FOXP3+ regulatory T cells (4.3-fold) and increase of CD4+ effector T cells (1.5-fold) compare with the control, and promotes damage associated molecular patterns generation to reinvigorate ICD effect. The potent antitumor of PDA-ICG@CAT-DTA-1 is proved in 4T1 bilateral tumor-bearing mice, with inhibition ratio of 95.1% for primary cancers and 68.7% for abscopal cancers. Our findings highlight great promise of the constructed versatility nanosystem to fix bottlenecks for cancer therapy.