Methicillin-resistant Staphylococcus aureus (MRSA) infections face significant clinical challenges such as antibiotic resistance and biofilm formation. It is necessary to develop novel antimicrobial strategies. In this study, we construct biomimetic antimicrobial peptides (BAMPs), i.e. Stearic acid-FFVLK-irikirik-NH2 (SAFI) and Linoleic acid-FFVLK-irikirik-NH2 (LAFI), to mimic the natural human defensin 6 that captures and kills invading bacteria. The peptides are designed with hydrophilic IRIKIRIK sequence for targeting and killing MRSA, FFVLK sequence for fibrillogenesis and hydrophobic chain. Both peptides exhibited potent antibacterial activity against MRSA and other Gram-positive bacteria with the MIC of 8 mu M, and inhibited biofilm formation. SEM and TEM images showed that peptides self-assembled into nanofibrous networks that physically entrapped MRSA cells. The peptides induced membrane depolarization, increased permeability, accompanied by ROS accumulation. In a murine full-thickness skin infection model, SAFI and LAFI induced significant bacterial reduction and comparable therapeutic efficacy to vancomycin. What's more, there was no local irritation or systemic toxicity during short-term topical use. The BAMPs show potential as alternatives to traditional antibiotics, particularly for topical applications in MRSA infections.

BACKGROUND:Distant metastases (DM) in differentiated thyroid carcinoma (DTC) are uncommon but markedly worsen patient prognosis. Existing risk prediction models frequently show limited accuracy because key clinicopathological predictors are not fully integrated. This study aimed to identify risk factors for DM and to develop a decision tree-based predictive model. MATERIALS AND METHODS:We retrospectively reviewed the medical records of 15,591 patients with DTC who underwent initial surgery at three tertiary centers between 2000 and 2018. Thirty-seven patients with DM and complete clinicopathological data constituted Cohort 1 (training set), whereas 14 comparable cases formed Cohort 2 (validation set). A 4:1 ratio-matched control group was generated by random sampling of patients with postoperative no evidence of disease (NED), matched for age, sex, and year of surgery. RESULTS:Univariate and multivariate analyses demonstrated significant differences (P < 0.001) between the DM and NED cohorts in median age, extrathyroidal extension (ETE), AJCC stage, tumor location, histological subtype, and primary tumor diameter. Decision tree and random forest analyses identified AJCC stage and tumor diameter as the most influential predictors of DM. A predictive model incorporating these variables achieved perfect classification accuracy, which was confirmed through external validation. In cases with metachronous metastases, histological subtype and ETE independently predicted survival outcomes. CONCLUSION:This study statistically optimized the weighting of risk factors for DM prediction in DTC, emphasizing AJCC stage and tumor diameter as dominant determinants. The resulting model demonstrated high accuracy and may support clinical decision-making for personalized patient management as a risk stratification tool.

The treatment of fibrinogen deficiency-related bleeding disorders and acquired hypofibrinogenemia remains heavily reliant on blood-derived products such as fibrinogen concentrate, a mainstay therapy constrained by limited supply, viral contamination risks, and high cost. Inspired by the natural blood clotting mechanism, this study designed an intelligent multifunctional biomimetic targeting and self-assembling peptide, i.e. SDGRG-C12-KLVFF-GRGDS (SC12FS). This peptide first self-assembled into nanoparticles mimicking fibrinogen to specifically target the activated platelet membrane glycoprotein GPIIb-IIIa receptor, inducing platelet aggregation and forming a loose primary hemostatic plug. Then, the nanoparticles would transform into nanofibers and further form interwoven fibrous networks with fibrin-like functionality by ligand-receptor-induced fibrillogenesis. These networks effectively entrap platelet aggregates and red blood cells, leading to the formation of a stable secondary clot. The biomimetic peptide showed the recovered hemostatic functionality and biosafety in the hypofibrinogenemia models of rats and rabbits following intravenous injection. This study provides a novel biomimetic material for safe, accessible hemostatic therapy, overcoming the dependence on human plasma sources for alleviating hypofibrinogenemia.

Tumor infarction is a promising treatment strategy that delivers benefits such as short therapeutic duration, low resistance potential, and broad applicability across diverse tumor types. However, treatments that induce vascular thrombosis cannot secure durable tumor elimination due to relapse caused by residual tumor cells (often localized in the surviving rim). To address this limitation, we combined tumor infarction therapy with chemotherapy and immunotherapy. Nonfocused ultrasound-targeted microbubble cavitation (UTMC) was used to induce vascular infarction by generating homogeneous and durable thrombosis while minimizing off-target damage. Simultaneously, redox-responsive liposomal camptothecin (CPT)-MSA-2 nanoparticles (CM NPs) were synthesized by coassembling sphingomyelin-derived CPT and the stimulator of interferon genes agonist MSA-2, which facilitates tumor-specific drug release in reductive microenvironments. Critically, CM NPs eradicated residual tumor cells that evaded infarction, thereby preventing recurrence. In murine tumor models, combining UTMC and CM NPs significantly enhanced therapeutic accumulation in tumors by 1.8-fold, suppressed primary tumor growth, eliminated recurrence, reduced lung metastasis by 71%, and extended median survival to 60 days, surpassing the therapeutic performance of all monotherapies. This multimodal strategy concurrently targets tumor vasculature, residual cells, and immunosuppression, thereby overcoming the limitations of conventional infarction therapy.

To compare the efficacy, safety and operational efficiency of radiofrequency-based transperineal thermal prostate ablation (TTPA) and single fiber transperineal laser ablation (TPLA) in patients with benign prostatic hyperplasia (BPH). Patients with moderate to severe lower urinary tract symptoms were included and divided into TTPA and TPLA groups. Changes in International Prostate Symptom Score (IPSS), quality of life (QoL), prostate volume (PV), post-void residual (PVR), and peak urine flow rate (Qmax) at 6 and 12 months were analyzed and compared between the two groups. Postoperative complications, operation time, ablation time were compared between the two groups. Thirty-six patients (20 TTPA vs 16 TPLA) were analyzed. At 12 months, the between-group difference in change in IPSS, QoL, PV, Qmax and PVR from baseline was − 1.59 (95

The cornea is a crucial refractive medium in the visual system, characterized by its avascular and transparent nature under physiological conditions. Pathological factors such as ocular trauma and inflammation can induce the formation of new capillaries from the limbal vascular network, leading to corneal neovascularization (CNV). With an associated blindness rate as high as 12%, CNV has become a significant challenge in ophthalmology. Current treatment strategies for CNV primarily include drug therapy such as anti-inflammatory and antiangiogenic agents, as well as surgical procedures like laser photocoagulation. These approaches are often limited by invasive procedures, suboptimal efficacy, and other constraints. Therefore, developing effective, safe, and convenient therapeutic options has become a critical research focus. Due to structural barriers of the ocular surface, the bioavailability of conventional eye drops is limited to ≈1%-5%, significantly restricting therapeutic efficacy. In recent years, researchers have been actively optimizing drug delivery systems using nanotechnology, hydrogels, and other advanced techniques to prolong ocular surface retention time, improve corneal penetration, and enhance drug release properties. This review summarizes recent advances in topical drug therapy for CNV, focusing on its pathogenesis, therapeutic agents, and delivery strategies, as well as approaches to enhance the bioavailability of topical treatments.

Anti-Gram-positive bacteria, including multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), face significant challenges due to their robust cell wall structures, biofilm formation, and resistance mechanisms. Natural antimicrobial peptides (NAMPs) with a long history of development and wide use in clinical applications demonstrate broad-spectrum antibacterial activities through multi-target mechanisms, including disrupting bacterial cell walls and membranes. Owing to methodological limitations, conventional approaches for discovering NAMPs are becoming less effective in identifying new candidates. Therefore, biomimetic antimicrobial peptides (BAMPs) have been developed through structural modifications to enhance stability, safety, and antimicrobial efficacy. This review systematically summarizes recent advances in NAMPs and BAMPs against Gram-positive bacteria, and describes their mechanisms of action, including targeting peptidoglycan precursors in bacterial cell walls, disrupting membrane integrity, and interfering with DNA/RNA to inhibit bacterial growth. This review emphasizes the bacterial trapping mechanism via in situ self-assembly. We also highlight molecular modifications to optimize BAMPs that improve their antimicrobial potential and expand their application in clinic. Finally, we discuss the current limitations and future perspectives of NAMPs and BAMPs, provide valuable guidance for designing next-generation antimicrobial agents.

ObjectiveTo predict post-thyroidectomy complications in papillary thyroid microcarcinoma (PTMC) patients using a deep learning model based on preoperative ultrasonographic features. This study addresses the global rise in PTMC incidence and the challenges in treatment decision-making with high-resolution ultrasonography.MethodThis study enrolled 1638 patients with clinically staged cN0 PTMC who received surgical treatment from 1997 to 2019 at Beijing Friendship Hospital. Deep learning model was developed using fully connected neural network. Feature selection included 1000 iterations of Bootstrap sampling and Recursive Feature Elimination (RFE) to identify the top 10 features. Data preprocessing involved normalization and imputation for missing values. SMOTE addressed class imbalance. The model was trained and tested on random data split, with performance metrics including Accuracy (ACC), Area Under the Curve (AUC), Sensitivity (SEN), and Specificity (SPE), visualized through a ROC curve and confusion matrix.ResultsThe fully connected deep neural network model demonstrated high accuracy (ACC 0.81), Area Under the Curve (AUC 0.74), sensitivity (SEN 0.65), and specificity (SPE 0.83) and visualized by ROC curve and confusion matrix. These results highlight the model's reliability and potential as an effective tool in predicting postoperative complications and assisting in clinical decision-making for PTMC patients.ConclusionThis study highlights the potential of deep learning in enhancing medical predictions and personalized healthcare. Despite promising results, limitations include a single-center data source and unconsidered factors like lifestyle and genetics. Future research should expand data sources, include more influencing factors, and refine algorithms to improve accuracy and applicability in thyroid cancer treatment. Our study underscores the potential of artificial intelligence, particularly artificial neural networks, in enhancing medical predictions. This AI model has the capability of forecast postoperative complications in cases of papillary thyroid microcarcinoma by analyzing preoperative ultrasonographic features, and demonstrated promising accuracy and reliability. This research paves the way for AI's more profound impact on personalized healthcare and surgical risk assessment. image

The extended use of androgen deprivation therapy (ADT) may often lead to the progression from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC) in prostate cancer. To address this, it is essential to inhibit the nuclear translocation of the androgen receptor (AR) as part of an effective disease-modifying strategy. Microtubules play a central role in facilitating AR nuclear translocation, highlighting their importance as a therapeutic target. In this regard, a designated as the targeted microtubules transformable nanopeptide system (MTN) is developed. This system is designed to disrupt microtubule structure and function through dual-targeting of prostate-specific membrane antigen (PSMA) and β-tubulin. Initially, MTN targets prostate cells via PSMA and then specifically binds to β-tubulin within microtubules, leading to the formation of nanofibers. These nanofibers subsequently induce the polymerization of microtubules, thereby disrupting AR transport. Notably, MTN exhibits efficient and prolonged suppression of prostate cancer across the spectrum from CSPC to CRPC, with a highly favorable safety profile in normal cells. These findings highlight the potential of MTN as a novel and promising approach for comprehensive prostate cancer therapy throughout its entire progression.

Efficient tumor-targeted drug delivery is still a challenging and currently unbreakable bottleneck in chemotherapy for tumors. Nanomedicines based on passive or active targeting strategy have not yet achieved convincing chemotherapeutic benefits in the clinic due to the tumor heterogeneity. Inspired by the efficient inflammatory-cell recruitment to acute clots, we constructed a two-component nanosystem, which is composed of an RGD-modified pyropheophorbide-a (Ppa) micelle (PPRM) that mediates the tumor vascular-targeted photodynamic reaction to activate local coagulation and subsequently transmits the coagulation signals to the circulating clot-targeted CREKA peptide-modified camptothecin (CPT)-loaded nanodiscs (CCNDs) for amplifying tumor targeting. PPRM could effectively bind with the tumor vasculature and induce sufficient local thrombus by a photodynamic reaction. Local photodynamic reaction-induced tumor target amplification greatly increased the tumor accumulation of CCND by 4.2 times, thus significantly enhancing the chemotherapeutic efficacy in the 4T1 breast tumor model. In other words, this study provides a powerful platform to amplify tumor-specific drug delivery by taking advantage of the efficient crosstalk between the PPRM-activated coagulation cascade and clot-targeted CCND.

Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8+ T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.

pH-dependent peptide biomaterials hold tremendous potential for cell delivery and tissue engineering. However, identification of responsive self-assembling sequences with specified secondary structure remains a challenge. In this work, An experimental procedure based on the one-bead one-compound (OBOC) combinatorial library is developed to rapidly screen self-assembling beta-sheet peptides at neutral aqueous solution (pH 7.5) and disassemble at weak acidic condition (pH 6.5). Using the hydrophobic fluorescent molecule thioflavin T (ThT) as a probe, resin beads displaying self-assembling peptides show fluorescence under pH 7.5 due to the insertion of ThT into the hydrophobic domain, and are further cultured in pH 6.5 solution. The beads with extinguished fluorescence are selected. Three heptapeptides are identified that can self-assemble into nanofibers or nanoparticles at pH 7.5 and disassemble at pH 6.5. P1 (LVEFRHY) shows a rapid acid response and morphology transformation with pH modulation. Changes in the charges of histidine and hydrophobic phenyl motif of phenylalanine may play important roles in the formation of pH-responsive beta-sheet nanofiber. This high-throughput screening method provides an efficient way to identify pH-dependent beta-sheet self-assembling peptide and gain insights into structural design of such nanomaterials. High-throughput one-bead one-compound (OBOC?screening strategy enables identification of pH-dependent self-assembling peptides with beta-sheet structure, providing insight into interactions between histidine and phenylalanine in the rational design of pH-dependent biomaterials.image

Abstract Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression, immunosurveillance, metastasis, and chemosensitivity. Particularly, in pancreatic ductal adenocarcinoma, tumor‐resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine (Gem) into its inactive form, thus rendering chemotherapy ineffective. Herein, a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model. An antimicrobial peptide was linked with photosensitizer through a poly (ethylene glycol) chain, which can self‐assemble into micelles with a diameter of ∼20 nm. The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization, thereby inhibiting Gem metabolism. In a bacteria‐resident pancreatic cancer animal model, the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance. This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.

Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem-like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self-renewal and stemness. A nanotherapeutic strategy is developed using tumor-penetrating peptide iRGD-modified high-density lipoprotein (HDL)-mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide-a (Ppa), bis (2-hydroxyethyl) disulfide (S-S), and camptothecin (CPT) by synthesizing two amphiphilic drug-conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self-renewal and trigger differentiation of the CSCs, while S-S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti-cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC-enriched heterogeneous colon tumor mouse models. Manipulating redox homeostasis of cancer stem cells induces differentiation by photoactivatable biomimetic nanodiscs. Ingeniously designed nanosystems with tumor deep penetration to target the cancer stem cells niches. Highly efficient combating cancer overcome CSCs-derived chemotherapeutic resistance. image

Peptide drugs are known for their high biological safety. However, compared with small molecule drugs, peptide drugs are easily oxidized and hydrolyzed as well as short in half-life. Herein, inspired by the long circulation of albumin in blood, we screened albumin binding peptides (ABPs) from a one -bead onecompound (OBOC) peptide library to increase the half-life of peptide drugs. Beads displaying random peptides were screened using fluorescent labeled human serum albumin. Fluorescent beads with specific binding to albumin were isolated for sequencing. The selected ABPs can effectively bind to albumin, thus possessing the long circulation of albumin. The dissociation constant (KD) of ABPs to albumin is up to 1 x 10-8 mol/L. Once one of ABPs (ABP2) was coupled to triptorelin, the circulation half-life of triptorelin in mice was significantly prolonged to 263.50 h much longer than that of triptorelin alone (179.07 h). In addition, the combination therapy using ABP -conjugated triptorelin and doxorubicin (DOX) can effectively inhibit the proliferation of tumor cells in mice. The OBOC screening strategy and resulting ABPs showed great potential for enhancing the delivery efficiency of peptide drugs. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

BACKGROUNDː Distant metastases (DM) occur rarely and are associated with poor outcomes in patients with differentiated thyroid carcinoma (DTC). The aim of this study was to explore potential risk factors of DM in DTC and build a decision-tree model. METHODSː The medical records of 15,591 patients who were diagnosed with DTC after initial surgery in three medical centers (2000 to 2018) were reviewed and 37 patients (test group) and 14 patients (validation group) with DM and detailed clinicopathologic characteristics were identified. Patients with no evidence of disease (NED) postoperatively were randomly sampled to create a control group in a 4:1 ratio. RESULTSː Multiple factors, including median age, extrathyroidal extension (ETE), AJCC stage, position, histological type, and diameter differed significantly between the DM and NED groups (P˂0.001) in univariate and multivariate analysis. AJCC stage and diameter of the primary tumor made the greatest contributions to prognosis according to decision-tree analysis and a random forest algorithm. The predictive model constructed from these data achieved 100% accuracy of classification. External validation confirmed that this model has 100% accuracy of classification. In addition, histology and ETE were found to be independent predictors of survival in patients with metachronous metastases. CONCLUSIONSː This study optimized the weight of risk factors, including AJCC stage and diameter of primary tumor, in predicting DM in patients with DTC. Our predictive model provides a strong tool for prediction that may potentially affect clinical decision-making.

Tumor infarction therapy is a promising antitumor strategy with the advantages of taking a short therapy duration, less risk of resistance, and effectiveness against a wide range of tumor types. However, its clinical application is largely hindered by tumor recurrence in the surviving rim and the potential risk of thromboembolic events due to nonspecific vasculature targeting. Herein, a neovasculature-targeting synthetic high-density lipoprotein (sHDL) nanodisc loaded with pyropheophorbide-a and camptothecin (CPN) was fabricated for photoactivatable tumor infarction and synergistic chemotherapy. By manipulating the anisotropy in ligand modification of sHDL nanodiscs, CPN modified with neovaculature-targeting peptide on the planes (PCPN) shows up to 7-fold higher cellular uptake compared with that around the edge (ECPN). PCPN can efficiently bind to endothelial cells of tumor vessels, and upon laser irradiation, massive local thrombus can be induced by the photodynamic reaction to deprive nutrition supply. Meanwhile, CPT could be released in response to the tumor reductive environment, thus killing residual tumor cells in the surviving rim to inhibit recurrence. These findings not only offer a powerful approach of synergistic cancer therapy but also suggest the potential of plane-modified sHDL nanodiscs as a versatile drug delivery nanocarrier.

Pancreatic carcinoma (PCa) is a malignant tumor that is highly lethal and lacks an effective treatment. Although surgical treatment, chemotherapy, and radiotherapy of PCa have undergone notable progress, the 5-year survival rate has not increased significantly. Minimally invasive techniques offer a promising alternative for unresectable local PCa, but their clinical application is limited by non-specific damage and low energy efficiency. To overcome these obstacles, nanoparticles as a medium or carrier to focus energy at the tumor site to kill tumor cells with the minimum dose and to limit side effects have been introduced. Nanomedicines combined with minimally invasive techniques alter the conventional therapeutic pattern and provide a new opportunity for PCa treatment. This review focuses on the application of nanomedicine to minimally invasive treatment of PCa and discusses the available options and future directions to improve patient survival.

4–1BB as a co-stimulatory receptor represents a next-generation therapeutic target in immune-oncology, which has been targeted by agonist antibodies or embedded in CAR-T cell construction. Notably, 4–1BB activation requires cluster formation due to natural ligand association. However, precise and robust regulation of receptor clustering still encounters great challenges. Herein, we report a rationally designed self-assembled peptide ligand, composed of targeting and assembly modules, for in situ triggering ligand-receptor complex aggregation and augmenting clustering on T cells. The unique peptide ligand structure imparts ligand inter-crosslinking (LIC) effect that i) augments assembly rate by 3-fold upon binding to specific receptor of interest, ii) stabilizes ligand-receptor complex compared to both monomeric ligand and ligand aggregates, iii) triggers enhancement of pro-inflammatory cytokine release, cell viability and phosphorylation of transcription factor compared to binding-only molecule. Finally, the ligand also supplements anti-PD-1 therapy alone in CT26 syngeneic murine tumor model with controllable toxicity risk.

Toll-like receptors (TLRs), found on antigen-presenting cells including macrophages and dendritic cells, are essential for identifying infections and initiating adaptive immunity. Therefore, among the many strategies for cancer immunotherapy, methods based on TLR agonists have been one of the most pursued directions. In addition to these immunologic activation functions, TLR agonists also contribute to reshaping immunosuppressive "cold" tumors into "hot" tumors. Despite their remarkable immunomodulatory properties, TLR agonists exhibit a low therapeutic index. Non-specific stimulation of various immune cells may produce excessive levels of inflammatory cytokines, leading to systemic side effects. The continuous development in nanotechnology has presented the possibility of innovative therapies to improve the efficacy and safety of TLR agonist-based immunotherapy. In this review, we describe the functions of TLRs in the tumor microenvironment, as well as, the pathways that activate immune responses, in addition to summarizing and discussing recent developments in nanotechnology for immunomodulation with TLR agonists, including platforms such as nanocapsules, micelles, liposomes, nanogels, and others. Nanotechnology can effectively improve the efficacy of TLR agonist-based immunotherapy, while playing a pivotal role in solving the limitations of the current treatment.