Natural Products from Herbal Medicine Self-Assemble into Advanced Bioactive Materials.

Novel biomaterials are becoming more crucial in treating human diseases. However, many materials require complex artificial modifications and synthesis, leading to potential difficulties in preparation, side effects, and clinical translation. Recently, significant progress has been achieved in terms of direct self-assembly of natural products from herbal medicine (NPHM), an important source for novel medications, resulting in a wide range of bioactive supramolecular materials including gels, and nanoparticles. The NPHM-based supramolecular bioactive materials are produced from renewable resources, are simple to prepare, and have demonstrated multi-functionality including slow-release, smart-responsive release, and especially possess powerful biological effects to treat various diseases. In this review, NPHM-based supramolecular bioactive materials have been revealed as an emerging, revolutionary, and promising strategy. The development, advantages, and limitations of NPHM, as well as the advantageous position of NPHM-based materials, are first reviewed. Subsequently, a systematic and comprehensive analysis of the self-assembly strategies specific to seven major classes of NPHM is highlighted. Insights into the influence of NPHM structural features on the formation of supramolecular materials are also provided. Finally, the drivers and preparations are summarized, emphasizing the biomedical applications, future scientific challenges, and opportunities, with the hope of igniting inspiration for future research and applications.

Flexible Sono-Piezo Patch for Functional Sweat Gland Repair through Endogenous Microenvironmental Remodeling.

Remodeling the endogenous regenerative microenvironment in wounds is crucial for achieving scarless, functional tissue regeneration, especially the functional recovery of skin appendages such as sweat glands in burn patients. However, current approaches mostly rely on the use of exogenous materials or chemicals to stimulate cell proliferation and migration, while the remodeling of a pro-regenerative microenvironment remains challenging. Herein, we developed a flexible sono-piezo patch (fSPP) that aims to create an endogenous regenerative microenvironment to promote the repair of sweat glands in burn wounds. This patch, composed of multifunctional fibers with embedded piezoelectric nanoparticles, utilized low-intensity pulsed ultrasound (LIPUS) to activate electrical stimulation of the target tissue, resulting in enhanced pro-regenerative behaviors of niche tissues and cells, including peripheral nerves, fibroblasts, and vasculatures. We further demonstrated the effective wound healing and regeneration of functional sweat glands in burn injuries solely through such physical stimulation. This noninvasive and drug-free therapeutic approach holds significant potential for the clinical treatment of burn injuries.

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer.

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

Impacts of TP53TG1 in cancer-associated fibroblasts-derived exosomes on epithelial-mesenchymal transition capacity of colorectal carcinoma cells by targeting miR-330-3p.

Objective: This research aims at clarifying the action and mechanisms of action of TP53TG1 in cancer-associated fibroblasts (CAF)-derived exosomes (EXs) on colorectal carcinoma (CRC) cells. Methods: CAF and CAF-EXs isolated from CRC tissues were incubated with CRC SW480 cells to determine alterations in biological behavior, epithelial-mesenchymal transition (EMT) capacity, and TP53TG1 and miR-330-3p expression. In addition, a dual luciferase reporter (DLR) assay was conducted to verify the connection between TP53TG1 and miR-330-3p, and the impacts of the two genes on CRC cells were analyzed. Results: CRC-CAF-EXs extracted from CRC tissues were successfully identified and were able to promote SW480 multiplication, invasiveness, migration, and EMT ability while inhibiting apoptosis (P < 0.05). In addition, TP53TG1 increased and miR-330-3p decreased in SW480 when cultured with CRC-CAF-EXs (P < 0.05). The DLR assay identified notably reduced fluorescence activity of TP53TG1-WT after transfection with miR-330-3p-mimics (P < 0.05). Furthermore, SW480 cell multiplication, invasiveness and migration were found to be enhanced and the apoptosis decreased after up-regulating TP53TG1, while suppressing TP53TG1 and up-regulating miR-330-3p contributed to quite the opposite effect (P < 0.05). Moreover, by elevating TP53TG1 and miR-330-3p simultaneously, we found a cell activity similar to the NC group (P > 0.05). Conclusion: By targeting miR-330-3p, TP53TG1 in CRC-CAF-EXs can enhance CRC cell activity and EMT capacity and inhibit apoptosis.

Investigating the role of TGF-ß and BDNF in cancer-related depression: a primary cross-sectional study.

BACKGROUND: Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-ß (TGF-ß), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-ß and BDNF in cancer-related depression. METHODS: This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-ß and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The study revealed elevated plasma TGF-ß levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-ß and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-ß and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-ß and BDNF between cancer and non-cancer groups (P = 0.041). CONCLUSIONS: These findings underscore the active involvement of TGF-ß and BDNF crosstalk in the context of cancer-related depression.

Customized Proteinaceous Nanoformulation for In Vivo Chemical Reprogramming.

Sweat gland (SwG) regeneration is crucial for the functional rehabilitation of burn patients. In vivo chemical reprogramming that harnessing the patient's own cells in damaged tissue is of substantial interest to regenerate organs endogenously by pharmacological manipulation, which could compensate for tissue loss in devastating diseases and injuries, for example, burns. However, achieving in vivo chemical reprogramming is challenging due to the low reprogramming efficiency and an unfavorable tissue environment. Herein, this work has developed a functionalized proteinaceous nanoformulation delivery system containing prefabricated epidermal growth factor structure for on-demand delivery of a cocktail of seven SwG reprogramming components to the dermal site. Such a chemical reprogramming system can efficiently induce the conversion of epidermal keratinocytes into SwG myoepithelial cells, resulting in successful in situ regeneration of functional SwGs. Notably, in vivo chemical reprogramming of SwGs is achieved for the first time with an impressive efficiency of 30.6%, surpassing previously reported efficiencies. Overall, this proteinaceous nanoformulation provides a platform for coordinating the target delivery of multiple pharmacological agents and facilitating in vivo SwG reprogramming by chemicals. This advancement greatly improves the clinical accessibility of in vivo reprogramming and offers a non-surgical, non-viral, and cell-free strategy for in situ SwG regeneration.

Deciphering the role of transcription factors in glioblastoma cancer stem cells.

Glioblastoma (GBM), the most aggressive and fatal brain malignancy, is largely driven by a subset of tumor cells known as cancer stem cells (CSCs). CSCs possess stem cell-like properties, including self-renewal, proliferation, and differentiation, making them pivotal for tumor initiation, invasion, metastasis, and overall tumor progression. The regulation of CSCs is primarily controlled by transcription factors (TFs) which regulate the expressions of genes involved in maintaining stemness and directing differentiation. This review aims to provide a comprehensive overview of the role of TFs in regulating CSCs in GBM. The discussion encompasses the definitions of CSCs and TFs, the significance of glioma stem cells (GSCs) in GBM, and how TFs regulate GSC self-renewal, proliferation, differentiation, and transformation. The potential for developing TF-targeted GSC therapies is also explored, along with future research directions. By understanding the regulation of GSCs by TFs, we may uncover novel diagnostic and therapeutic strategies against this devastating disease of GBM.

Per- and polyfluoroalkyl substances (PFAS) exposure in plasma and their blood-brain barrier transmission efficiency-A pilot study.

Per- and polyfluoroalkyl substances (PFAS) have been shown to penetrate the blood-brain barrier (BBB) and accumulate in human brain. The BBB transmission and accumulation efficiency of PFAS, as well as the potential health risks from human co-exposure to legacy and emerging PFAS due to differences in transport efficiency, need to be further elucidated. In the present pilot study, 23 plasma samples from glioma patients were analyzed for 17 PFAS. The concentrations of PFAS in six paired brain tissue and plasma samples were used to calculate the BBB transmission efficiency of PFAS (RPFAS). This RPFAS analysis was conducted with utmost care and consideration amid the limited availability of valuable paired samples. The results indicated that low molecular weight PFAS, including short-chain and emerging PFAS, may have a greater potential for accumulation in brain tissue than long-chain PFAS. As an alternative to perfluorooctane sulfonic acid (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) exhibited brain accumulation potential similar to that of PFOS, suggesting it may not be a suitable substitute concerning health risk in brain. The BBB transmission efficiencies of perfluorooctanoic acid, PFOS, and 6:2 Cl-PFESA showed similar trends with age, which may be an important factor influencing the entry of exogenous compounds into the brain. A favorable link between perfluorooctane sulfonamide (FOSA) and the development and/or progression of glioma may be implicated by a strong positive correlation (r2 = 0.94; p < 0.01) between RFOSA and Ki-67 (a molecular marker of glioma). However, a causal relationship between RFOSA and glioma incidence were not established in the present study. The present pilot study conducted the first examination of BBB transmission efficiency of PFAS from plasma to brain tissue and highlighted the importance of reducing and/or controlling exposure to PFAS.

Imaging and Liquid Biopsy for Distinguishing True Progression From Pseudoprogression in Gliomas, Current Advances and Challenges.

RATIONALE AND OBJECTIVES: Gliomas are aggressive brain tumors with a poor prognosis. Assessing treatment response is challenging because magnetic resonance imaging (MRI) may not distinguish true progression (TP) from pseudoprogression (PsP). This review aims to discuss imaging techniques and liquid biopsies used to distinguish TP from PsP. MATERIALS AND METHODS: This review synthesizes existing literature to examine advances in imaging techniques, such as magnetic resonance diffusion imaging (MRDI), perfusion-weighted imaging (PWI) MRI, and liquid biopsies, for identifying TP or PsP through tumor markers and tissue characteristics. RESULTS: Advanced imaging techniques, including MRDI and PWI MRI, have proven effective in delineating tumor tissue properties, offering valuable insights into glioma behavior. Similarly, liquid biopsy has emerged as a potent tool for identifying tumor-derived markers in biofluids, offering a non-invasive glimpse into tumor evolution. Despite their promise, these methodologies grapple with significant challenges. Their sensitivity remains inconsistent, complicating the accurate differentiation between TP and PSP. Furthermore, the absence of standardized protocols across platforms impedes the reliability of comparisons, while inherent biological variability adds complexity to data interpretation. CONCLUSION: Their potential applications have been highlighted, but gaps remain before routine clinical use. Further research is needed to develop and validate these promising methods for distinguishing TP from PsP in gliomas.

Pollution levels and probability risk assessment of potential toxic elements in soil of Pb-Zn smelting areas.

Soil pollution around Pb-Zn smelters has attracted widespread attention around the world. In this study, we compiled a database of eight potentially toxic elements (PTEs) Pb, Zn, Cd, As, Cr, Ni, Cu, and Mn in the soil of Pb-Zn smelting areas by screening the published research papers from 2000 to 2023. The pollution assessment and risk screening of eight PTEs were carried out by geo-accumulation index (Igeo), potential ecological risk index (PERI) and health risk assessment model, and Monte Carlo simulation employed to further evaluate the probabilistic health risks. The results suggested that the mean values of the eight PTEs all exceeded the corresponding values in the upper crust, and more than 60% of the study sites had serious Pb and Cd pollution (Igeo > 4), with Brazil, Belgium, China, France and Slovenia having higher levels of pollution than other regions. Besides, PTEs in smelting area caused serious ecological risk (PERI = 10912.12), in which Cd was the main contributor to PREI (86.02%). The average hazard index (HI) of the eight PTEs for adults and children was 7.19 and 9.73, respectively, and the average value of total carcinogenic risk (TCR) was 4.20 × 10-3 and 8.05 × 10-4, respectively. Pb and As are the main contributors to non-carcinogenic risk, while Cu and As are the main contributors to carcinogenic risk. The probability of non-carcinogenic risk in adults and children was 84.05% and 97.57%, while carcinogenic risk was 92.56% and 79.73%, respectively. In summary, there are high ecological and health risks of PTEs in the soil of Pb-Zn smelting areas, and Pb, Cd, As and Cu are the key elements that cause contamination and risk, which need to be paid attention to and controlled. This study is expected to provide guidance for soil remediation in Pb-Zn smelting areas.

Development of a risk estimation model for condomless sex among college students in Zhuhai, China: a cross-sectional study.

BACKGROUND: Condom use at last intercourse is an effective indicator for human immunodeficiency virus (HIV) prevention. To identify at-risk individuals and improve prevention strategies, this study explored factors associated with condomless sex at last intercourse in the last year and developed a risk estimation model to calculate the individual possibility of condomless sex among college students in Zhuhai, China. METHODS: A cross-sectional study was conducted among 1430 college students who had sex in the last year from six universities in Zhuhai. The least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to explore the predictors of condomless sex. The nomogram was constructed to calculate the individual possibility of condomless sex. Discrimination and calibration of the nomogram were evaluated using the area under the receiver-operator characteristic curve (AUROC) and the calibration curve. RESULTS: The proportion of students who had condomless sex at last intercourse was 18.2% (260/1430). Students who had experienced more types of intimate partner violence (aOR, 1.58; 95% CI, 1.31 ~ 1.92) and had anal sex (aOR, 1.75; 95% CI, 1.06 ~ 2.84) were more likely to have condomless sex. Students who had heterosexual intercourse (aOR, 0.37; 95% CI, 0.21 ~ 0.70), used condoms at first sex (aOR, 0.20; 95% CI, 0.14 ~ 0.27), had high attitudes towards condom use (aOR, 0.87; 95% CI, 0.80 ~ 0.95) and self-efficacy for condom use (aOR, 0.84; 95% CI, 0.78 ~ 0.90) were less likely to have condomless sex. The nomogram had high accuracy with an AUROC of 0.83 and good discrimination. CONCLUSIONS: Intimate partner violence, anal sex, condom use at first sex, attitude towards condom use, and self-efficacy for condom use were associated with condomless sex among college students. The nomogram was an effective and convenient tool for calculating the individualized possibility of condomless sex among college students. It could help to identify individuals at risk and help universities and colleges to formulate appropriate individualized interventions and sexual health education programs.

Modular Protein Fibers with Outstanding High-Strength and Acid-Resistance Performance Mediated by Copper Ion Binding and Imine Networking.

Engineered protein fibers are promising biomaterials with diverse applications due to their tunable protein structure and outstanding mechanical properties. However, it remains challenging at the molecular level to achieve satisfied mechanical properties and environmental tolerance simultaneously, especially under extreme acid conditions. Herein, the construction of artificial fibers comprising chimeric proteins made of rigid amyloid peptide and flexible cationic elastin-like protein (ELP) module is reported. The amyloid peptide readily assembles into highly organized ß-sheet structures that can be further strengthened by the coordination of Cu2+, while the flexible ELP module allows the formation of imine-based crosslinking networks. These double networks synergistically enhance the mechanical properties of the fibers, leading to a high tensile strength and toughness, overwhelming many reported recombinant spidroin fibers. Notably, the coordination of Cu2+ with serine residues could stabilize ß-sheet structures in the fibers under acidic conditions, which makes the fibers robust against acid, thus enabling their successful utilization in gastric perforation suturing. This work highlights the customization of double networks at the molecular level to create tailored high-performance protein fibers for various application scenarios.

Molecular insight into the enhanced performance of CALB toward PBDF degradation.

Poly(butylene diglycolate-co-furandicarboxylate) (PBDF) is a newly developed biodegradable copolyester. Candida antarctica lipase B (CALB) has been identified as an effective catalyst for PBDF degradation. The mechanism is elucidated using a combination of molecular dynamics simulations and quantum chemistry approaches. The findings unveil a four-step catalytic reaction pathway. Furthermore, bond analysis, charge and interaction analysis are conducted to gain a more comprehensive understanding of the PBDF degradation process. Additionally, through the introduction of single-point mutations to crucial residues in CALB's active sites, two mutants, T138I and D134I, are discovered to exhibit improved catalytic efficiency. These significant findings contribute to the advancement of our comprehension concerning the molecular mechanism of underlying copolyesters degradation, while also presenting a novel approach for expediting the degradation rate by the CALB enzyme modification.

Preoperative Prediction of Perineural Invasion and Prognosis in Gastric Cancer Based on Machine Learning through a Radiomics-Clinicopathological Nomogram.

PURPOSE: The aim of this study was to construct and validate a nomogram for preoperatively predicting perineural invasion (PNI) in gastric cancer based on machine learning, and to investigate the impact of PNI on the overall survival (OS) of gastric cancer patients. METHODS: Data were collected from 162 gastric patients and analyzed retrospectively, and radiomics features were extracted from contrast-enhanced computed tomography (CECT) scans. A group of 42 patients from the Cancer Imaging Archive (TCIA) were selected as the validation set. Univariable and multivariable analyses were used to analyze the risk factors for PNI. The t-test, Max-Relevance and Min-Redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select radiomics features. Radscores were calculated and logistic regression was applied to construct predictive models. A nomogram was developed by combining clinicopathological risk factors and the radscore. The area under the curve (AUC) values of receiver operating characteristic (ROC) curves, calibration curves and clinical decision curves were employed to evaluate the performance of the models. Kaplan-Meier analysis was used to study the impact of PNI on OS. RESULTS: The univariable and multivariable analyses showed that the T stage, N stage and radscore were independent risk factors for PNI (p < 0.05). A nomogram based on the T stage, N stage and radscore was developed. The AUC of the combined model yielded 0.851 in the training set, 0.842 in the testing set and 0.813 in the validation set. The Kaplan-Meier analysis showed a statistically significant difference in OS between the PNI group and the non-PNI group (p < 0.05). CONCLUSIONS: A machine learning-based radiomics-clinicopathological model could effectively predict PNI in gastric cancer preoperatively through a non-invasive approach, and gastric cancer patients with PNI had relatively poor prognoses.

Electrophoretic Deposition of Single Nanoparticles.

The controlled assembly of colloid particles on a solid substrate has always been a major challenge in colloid and surface science. Here we provide an overview of electrophoretic deposition (EPD) of single charge-stabilized nanoparticles. We demonstrate that surface templated EPD (STEPD) assembly, which combines EPD with top-down nanofabrication, allows a wide range of nanoparticles to be built up into arbitrary structures with high speed, scalability, and excellent fidelity. We will also discuss some of the current colloid chemical limitations and challenges in STEPD assembly for sub-10 nm nanoparticles and for the fabrication of densely packed single particle arrays.

Steric repulsion introduced by loop constraints modulates the microphase separation of chromatins.

Within the confines of a densely populated cell nucleus, chromatin undergoes intricate folding, forming loops, domains, and compartments under the governance of topological constraints and phase separation. This coordinated process inevitably introduces interference between different folding strategies. In this study, we model interphase chromatins as block copolymers with hetero-hierarchical loops within a confined system. Employing dissipative particle dynamics simulations and scaling analysis, we aim to explain how the structure and distribution of loop domains modulate the microphase separation of chromatins. Our results highlight the correlation between the microphase separation of the copolymer and the length, heterogeneity, and hierarchically nested levels of the loop domains. This correlation arises from steric repulsion intrinsic to loop domains. The steric repulsion induces variations in chain stiffness (including local orientation correlations and the persistence length), thereby influencing the degree of phase separation. Through simulations of block copolymers with distinct groups of hetero-hierarchical loop anchors, we successfully reproduce changes in phase separation across diverse cell lines, under fixed interaction parameters. These findings, in qualitative alignment with Hi-C data, suggest that the variations of loop constraints alone possess the capacity to regulate higher-order structures and the gene expressions of interphase chromatins.

Electrochemical Biosensor for Protein Concentration Monitoring Using Natural Wood Evaporation for Power Generation.

A high-sensitivity, low-cost, self-powered biomass electrochemical biosensor based on the "evaporating potential" theory is developed for protein detection. The feasibility of experimental evaluation methods was verified with a probe protein of bovine serum albumin. The sensor was then used to detect lung cancer marker CYFRA21-1, and the potential of our sensor for clinical diagnosis was demonstrated by serum analysis. This work innovatively exploits the osmotic power generation capability of natural wood to construct a promising electrochemical biosensor that was driven by kinetics during testing. The detection methods used for this sensor, chronoamperometry and AC impedance, showed potential for quantitative analysis and specific detection, respectively. Furthermore, the sensor could facilitate new insights into the development of high-sensitivity, low-cost, and easy-to-use electrochemical biosensors.

Single-nucleus multi-omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy.

The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.

Covalent organic frameworks with flexible side chains in hybrid PEMs enable highly efficient proton conductivity.

Electrochemical hydrogen compression (EHC) is an emerging energy conversion technology. Proton exchange membranes (PEMs) with high proton conductivity and high mechanical strength are highly required to meet the practical requirements of EHC. Herein, ionic covalent organic frameworks (iCOFs) with tunable side chains were synthesized and introduced into the sulfonated poly (ether ether ketone) (SPEEK) matrix to fabricate hybrid PEMs. In our membranes, the rigid iCOFs afford ordered proton conduction channels, whereas the flexible side chains on iCOFs afford abundant proton conduction sites, adaptive hydrogen bonding networks, and high local density short hydrogen bonds for highly efficient proton transport. Moreover, the hydrogen bond interactions between the side chains on iCOFs and the SPEEK matrix enhance the mechanical stability of membranes. As a result, the hybrid PEM acquires an enhanced proton conductivity of 540.4 mS cm-1 (80 °C, 100%RH), a high mechanical strength of 120.41 MPa, and a superior performance (2.3 MPa at 30 °C, 100%RH) in EHC applications.