Chikungunya virus (CHIKV), an alphavirus transmitted by Aedes mosquitoes, has frequently caused outbreaks in tropical and subtropical regions worldwide, posing a significant public health threat. CHIKV infection leads to chikungunya fever, characterized by fever, rash, and persistent joint pain, with approximately 30%-40% of patients developing chronic arthritis that severely impacts quality of life. Currently, no specific antiviral drugs or vaccines against CHIKV have been approved for clinical use, highlighting the urgency of drug development. This review systematically summarizes recent progress in antiviral research on CHIKV, focusing on key target proteins in the viral life cycle, such as non-structural proteins nsP1, nsP2, nsP3, nsP4, and structural protein E1-E2 complexes, as well as the mechanisms of action of their inhibitors. We analyze the current research status of various anti-CHIKV compounds, including suramin, baicalin, halofuginone, betulinic acid, andrographolide, and itraconazole. Additionally, we summarize host-directed antiviral strategies targeting pathways such as host cell oxidative folding, Na⁺/K⁺-ATPase, and MAPK signaling. This review aims to establish a theoretical foundation and outline potential research directions for the development of CHIKV-related therapeutics, thereby facilitating the discovery of effective treatment strategies against this pathogen.

The field of cancer immunotherapy has undergone significant advancements in recent years, leading to a paradigm shift in treatment methodologies. However, “cold” tumors, characterized by low immune cell infiltration and an immunosuppressive tumor microenvironment (TME), present considerable therapeutic challenges. In contrast to “hot” tumors, which exhibit vigorous immune activity and responsiveness to immune checkpoint inhibitors, “cold” tumors evade immune surveillance through mechanisms such as impaired antigen expression and restricted T-lymphocyte infiltration. This immune evasion is closely linked to the dysregulation of cytokines and chemokines, which shape the TME and orchestrate immune responses. This review delineates the immune escape mechanisms of cold tumors, with particular emphasis on the role of cytokines/chemokines in modulating the TME. Here we will explore advanced therapeutic strategies that employ engineered chemokines/cytokines (e.g., IL-2 muteins such as Neo-2/15, IL-15/IL-15Rα complexes, and CAR-T cells expressing CXCL9/10), nanoparticle-based delivery systems (e.g., lipid nanoparticles, PLGA nanoparticles, and chitosan-based carriers for targeted cytokine/chemokine delivery), and combination therapies. These strategies aim to remodel the TME to enhance immune infiltration. Emerging therapies designed to transform cold tumors into immunologically active phenotypes through the modulation of cytokines and chemokines are discussed. Finally, the review highlights the ongoing challenges and future directions in using cytokine/chemokine modulation to overcome the limitations of current treatments, emphasizing their transformative potential in addressing the unmet needs of cancer immunotherapy.

Frizzled receptors (FZDs) have emerged as pivotal regulators in cancer biology, orchestrating key oncogenic processes such as tumor metastasis, therapy resistance, and stemness through canonical WNT/β-catenin and noncanonical WNT/PCP and WNT/Ca²⁺ signaling pathways. Their overexpression in diverse malignancies and cell surface localization make FZDs compelling therapeutic targets. Yet, clinical translation of FZD-targeted therapies has been hindered by limited efficacy and poor subtype specificity of FZD orthosteric inhibitors. In this review, we provide a comprehensive and systematic analysis of FZD biology by tracing its discovery history, elucidating its conserved structural features, and deciphering its context-dependent roles in WNT signaling. We propose novel insights into the multifaceted roles of FZD in tumorigenesis, positioning it as a driver of cancer progression. We emphasize the urgent need for developing subtype-selective targeting strategies for FZD, critically assess the challenges of achieving binding specificity within highly homologous extracellular domains, and summarize cutting-edge advances in structure-based design of FZD negative allosteric modulators. This study establishes a strategic framework for precision targeting of the FZD family, paving the way for developing more efficient, mechanism-driven, and potentially transformative anticancer therapies.

The rising global cancer burden underscores the urgent need for more effective drug development and personalized therapies. Conventional screening models, such as 2D cell lines and patient-derived xenografts, fail to adequately recapitulate the architecture, heterogeneity, and microenvironment of human tumors, limiting their clinical translatability. In response, human-derived biomimetic platforms have emerged. Organoids and organ-on-a-chip preserve key tumor genetics and stimulate dynamic, physiologically relevant microenvironments, whereas microtumors are distinguished by high biological fidelity. Microtumors uniquely retain the native tumor ecosystem, capture a broader spectrum of intratumoral heterogeneity, and, critically, maintain a functional immune microenvironment. Together, these systems enable drug screening that more faithfully reflects the clinical context, with strong potential to raise drug development success rates and support individualized therapy. This review consolidates the cutting-edge advancements and critical challenges associated with these models in drug development, precision medicine, and clinical translation. Furthermore, it envisions how Artificial Intelligence (AI) can drive its intelligent evolution, aiming to provide a robust evidentiary basis and practical reference for research and clinical practice, thereby propelling the field of precision oncology into a new era.

The global rise of antimicrobial resistance calls for new therapeutic approaches that move beyond conventional broad-spectrum antibiotics toward precision-guided nanotherapeutics. This review examines how smart antibacterial nanomedicines achieve better therapeutic outcomes through two key control dimensions: Spatial precision (where) and temporal activation (when). We first discuss active targeting strategies that direct therapeutic payloads to infection sites while sparing healthy tissues. We then analyze microenvironment-responsive mechanisms that keep therapeutic agents inactive until they encounter specific pathological signals. Moving beyond a simple catalog of material properties, we propose a “Hierarchical Intelligence Framework” that organizes nanoparticles along a spectrum of increasing complexity—from basic ligand-guided systems to integrated, logic-responsive nanodevices operating through “Target-Trigger-Treat” protocols. By examining design principles and practical challenges in pharmaceutical development, this work outlines a path toward resistance-overcoming nanomedicines that may reshape infection management in the coming decades.

Alopecia profoundly impacts an individual’s appearance, quality of life, and social well-being, with its prevalence increasing with age. Conventional treatments, such as topical minoxidil and oral finasteride, suffer from limitations like inefficient drug delivery, side effects, and inconsistent efficacy. Other therapies, like hair transplantation, biologics and low-level laser therapy (LLLT), also face some constraints in practical application. Microneedles (MNs), as an emerging transdermal drug delivery system (TDDS), enable efficient local delivery of therapeutic agents to hair follicles in the balding scalp by physically penetrate stratum corneum. Through enhanced drug permeability and activation of follicular regeneration pathways, MN-combined strategies have ignited considerable research interest. This review outlines the advances in MN-mediated alopecia treatments over the past five years and underscores their potential to enhance hair regrowth efficacy, including MN-assisted delivery of chemical drugs, natural compounds, biologics, nanomedicines, stem cells, and LLLT. Additionally, this review also summarizes the advances in clinical trials of MN-combined therapies for alopecia over the past five years, highlighting the noticeable disconnection in research focus between basic research and clinical trials. In summary, this review aims to provide critical insights and future perspectives for the development of MN-integrated therapies for alopecia management.

Advances in cancer therapy have underscored the critical need for multifunctional platforms that enable precise targeting, controlled drug release, and immunomodulation. Hydrogels, as transformative tools with programmable drug release capabilities, microenvironmental responsiveness, and immunoregulatory properties, demonstrate broad application prospects. This review focuses on the design and application of functionalized hydrogels, emphasizing their responsiveness to multiple stimuli, including temperature, pH, reactive oxygen species (ROS), and enzymes. It provides an in-depth analysis of their multimodal synergistic therapeutic mechanisms, including photothermal therapy, immunotherapy, starvation therapy, intelligent detection, targeted capture, and tumor microenvironment (TME) simulation. Meanwhile, recent developments in machine learning-enabled intelligent hydrogel technologies have driven the transformation of materials into intelligent systems with “smart design-perception-decision” capabilities. Although the literature on smart hydrogels has made significant progress in exploring mechanisms and optimizing performance, systematic reviews of artificial intelligence (AI)-driven platforms remain notably lacking. This paper systematically summarizes the regulatory strategies of material-derived intelligent hydrogels, AI-enabled mechanisms, and practical application cases, revealing core challenges and future development directions, thereby providing theoretical guidance and practical pathways for next-generation hydrogels in personalized and multimodal cancer therapy.

Cellular senescence is a state of cell cycle arrest caused by various types of stress, and it is characterized by morphological changes, metabolic reprogramming, and the release of the senescence-associated secretory phenotype (SASP). In cancer therapy, senescence plays a complex role by inhibiting cancer progression, mediating metabolic imbalance, modulating local immune responses, and restructuring the cancer microenvironment. These mechanisms have been harnessed to develop nano-drug delivery systems (Nano-DDSs)-based combination therapies for cancer. We systematically explain key biological features of cellular senescence and detail recent advances in creating drug delivery systems aimed at targeting cancer senescence through these four mechanisms. Additionally, we discuss the clinical challenges in translating senescence-targeting strategies with Nano-DDSs and propose future directions within an interdisciplinary framework. This review offers valuable insights into designing advanced Nano-DDSs based on the multidimensional regulatory mechanisms of cellular senescence and their application in cancer treatment.

Inflammation is a complex and dynamic immune response triggered by tissue injury or pathogen invasion, playing a critical role in restoring tissue homeostasis. However, excessive inflammation can lead to tissue damage and exacerbate the progression of various diseases. Issues such as off-target effects and insufficient dynamic regulation pose key challenges to precise modulation of complex inflammatory processes, thereby enhancing efficacy while minimizing adverse effects. Engineered cell-biomimetic nanosystems (ECNs), including membrane-coated nanoparticles, extracellular vesicles (ECVs), and cell-nanoparticle hybrids, are highly adaptable biomimetic platforms with tunable physicochemical properties. Beyond carrier functions, ECNs are capable of actively responding to inflammation-related targets and interacting with the immune microenvironment, thereby promoting the dynamic regulation of inflammation. This review summarizes recent advances in ECNs, with an emphasis on targeting mechanisms and key strategies for inflammatory intervention. These include precise targeting of inflamed tissues, biological neutralization of toxins and overexpressed inflammatory factors to interrupt the inflammatory cascade, and immunomodulatory functions that balance immune responses to achieve activation or suppression. Physical, chemical, and biological engineering strategies for modifying cells and cell membranes for inflammation targeting are also discussed. As an emerging platform for targeted drug delivery and immune regulation, ECNs provide innovative technological approaches for inflammation therapy.

Cancer treatment has advanced significantly over the past few decades, resulting in improved patient survival outcomes. However, challenges like drug resistance, off-target effects, and systemic toxicity continue to persist. These underscore the importance of modified extracellular vesicles (EVs) as a versatile and innovative platform for delivering combination therapies for cancer. This review highlights the utilization of biocompatible engineered EVs to inhibit cancer progression with reduced side effects. Further, outlining the promising approach to cancer treatment through combination therapies and imaging-guided strategies. Additionally, this review explored the biogenesis and various sources of EVs, which provides clear insights into future directions.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses growing global health and socioeconomic challenges due to aging populations and limited therapeutic efficacy. Current treatments, including cholinesterase inhibitors and anti-amyloid monoclonal antibodies, can only delay disease progression without reversing pathology. Emphasizing on prevention, this review provides key updates on advancements in the pathogenesis, diagnosis, and intervention of AD highlighting preventive strategies that can target modifiable risk factors. Key findings underscore the role of managing hypertension and diabetes, optimizing trace elements, vitamins, and regular physical exercise in mitigating the risk of AD. Biomarker-based early diagnosis and emerging therapies provide further support for proactive intervention. Future challenges include the long-term validation of preventive measures and policy-driven funding for large-scale cohort studies. Prioritizing prevention through lifestyle modifications, nutritional balance, and precision medicine is pivotal to reduce the burden of AD in aging societies.

Idiosyncratic drug-induced liver injury (iDILI) is a rare, dose-independent and unpredictable adverse reaction occurring at therapeutic drug exposure, and it presents a significant challenge for drug development and patient safety. Despite extensive research, genetic susceptibility to iDILI remains poorly understood. We conducted a comprehensive systematic study of 139 human genetic studies to identify and characterize genetic polymorphisms associated with increased risk or protection against iDILI. Our study included candidate gene studies and genome-wide association studies (GWAS), encompassing 83 risk and 25 protective genes, with NAT2, HLA-B, and SLCO1B1 among the most frequently reported. We performed functional enrichment analyses using KEGG and Gene Ontology, revealing key biological pathways related to immune response, xenobiotic metabolism, and bile secretion. To enhance data accessibility and interpretation, we developed iDILInet, a publicly available web application that enables interactive exploration and network-based visualization of iDILI-associated gene-variant-drug relationships, enriched with liver-specific expression data from the Human Protein Atlas (HPA). Our work provides a novel integrative resource that supports ongoing efforts in precision medicine and pharmacogenomics and represents a significant advancement in implementing living systematic reviews in toxicogenomics.

The reduction of dead/dying neurons represents a critical mechanism for the anti-acute ischemic stroke (AIS) effect of Panax notoginseng, however, its molecular basis remains unclear. Recent findings implicate chemokine-like factor 1 (CKLF1) as a key contributor to the impaired clearance of dying neurons. Here, we established an integrated high-throughput screening strategy combining biolayer interferometry (BLI), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and NanoBRET technologies to identify CKLF1 inhibitors among Panax notoginseng saponins (PNS). Of note, ginsenoside Rg1 (GRg1) exhibits the highest affinity for CKLF1 and the most potent inhibitory efficacy against the CKLF1-CCR4 interaction, effectively suppressing CKLF1-C27 peptide-induced calcium influx and cytokine production. In experimental AIS models, GRg1 confers neuroprotective properties by mitigating ischemic brain damage and promoting neuronal functional recovery. Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons. This study presents an efficient approach for the discovery of natural CKLF1 inhibitors and highlights GRg1 as a promising therapeutic candidate for enhancing the clearance of dead/dying neurons in AIS.

Epigenetic reprogramming underpins trained immunity (TRIM). However, the importance of mRNA reprogramming in TRIM remains unknown. Here, we discovered, for the first time, that the steroid hormone ouabain creates a significant training effect on peripheral innate immune cells (IICs), leading to functional enhancement of IICs against bacterial infections. However, unlike conventional training mechanisms, ouabain primarily relies on an integrated posttranscriptional RNA regulon complex (IPRRC) to establish immune memory and reprogram cytokine expression, with lncRNA-CYTOR playing a critical role in this process. Moreover, to enhance training effects while reducing lactate production, ouabain promotes a rapid degradation of the Na⁺,K⁺-ATPase receptor. Pathologically, endogenous ouabain is downregulated in sepsis-induced immunoparalysis in vivo, correlating with impaired innate immunity. Exogenous ouabain rescue significantly reverses this impairment, and its effect is superior to β-glucan, even when used at one percent of β-glucan dosage. Notably, posttranscriptional RNA regulons are also critically involved in β-glucan’s training effects. Overall, mRNA reprogramming emerges as a new mechanism for TRIM; steroid hormone ouabain is a novel innate immunity regulator.

Tumor-associated macrophages (TAMs) are pivotal drivers of hepatocellular carcinoma (HCC) progression, and blocking TAM M2 polarization has the potential to dampen tumor microenvironment remodeling. In this study, we screened a series of phenylethanoid and phenylpropanoid glycosides and identified syringin as a natural compound capable of inhibiting M2 polarization while promoting M1 polarization in macrophages. Single-cell RNA sequencing confirmed that syringin reduced TAM M2 polarization and significantly impaired tumor microenvironment remodeling. In detail, syringin indirectly reduced the stability of MYC proto-oncogene protein (MYC), which is required for driving a broad set of targets, including Arg1, Il10, Ym1, Mrc1, and Cd274. Using affinity-based protein profiling (ABPP), we revealed dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of syringin. DLAT possesses protein acetyltransferase activity that acetylates MYC at K148. Syringin bound DLAT at residues R430 and N576 and disrupted the DLAT/MYC axis, thereby blocking MYC acetylation and promoting the ubiquitination and degradation of MYC protein. Additionally, syringin enhanced the efficacy of programmed cell death protein 1 blockade in mouse and patient-derived xenograft models, offering a potential adjunctive agent for HCC.

Triple-negative breast cancer (TNBC) exhibits marked molecular heterogeneity, posing ongoing therapeutic challenges. Metabolic reprogramming, particularly through the Warburg effect, offers a promising therapeutic target for TNBC treatment. Data mining and machine learning identified (+)-miliusol as a promising candidate. Its direct target, eukaryotic initiation factor 3D (EIF3D), was validated through mass spectrometry-coupled cellular thermal shift assay (MS-CETSA), a biotinylated probe, and a proteolysis-targeting chimera (PROTAC) approach. EIF3D, an emerging oncoprotein and atypical translation initiation regulator, promotes tumor survival by selectively modulating protein synthesis. (+)-Miliusol demonstrates potent anti-proliferative and anti-migratory activity against TNBC in both in vitro and in vivo. Integrated proteomic and transcriptomic analyses revealed that (+)-miliusol suppresses TNBC progression through EIF3D-mediated translational regulation. Mechanistically, it disrupts the EIF3D-AlkB homolog 5 (ALKBH5)-glucose transporter type 4 (GLUT4) axis, EIF3D-HIF1α signaling, and the EIF3D-RuvB like AAA ATPase 1 (RUVBL1)-β-catenin pathway, thereby inhibiting glycolysis and metastasis while inducing ER stress-dependent apoptosis via caspase-12 and JNK activation. Additionally, (+)-miliusol blocks EIF3D-HIF1α and EIF3D-ALKBH3 interactions, impairing ATAD2/PAK1-regulated Warburg-effect networks and triggering autophagy-associated cell death. (+)-Miliusol induces TNBC cell death by selectively suppressing translation of critical glycolytic and metastatic regulators. These findings establish EIF3D-mediated translational control as a promising therapeutic avenue for TNBC treatment.

Metastases are a primary cause of cancer-associated mortality; however, the mechanisms underlying aggressive progression have not been clearly elucidated. Genome-wide features of chromatin accessibility through ATAC-seq from HCC primary and metastatic tumors revealed that many distal regulatory elements spreading the genome become accessible during aggressive progression, the changes of which are associated with NFY-family. And NFYB is frequently upregulated in tumor with metastasis. Mechanistically, LINC01137 recruits SMYD3 to enhance H3K4me3 occupancy at IL-1β, CXCL2 and CCL20 promoters by inhibiting lysine ubiquitination to stabilize NFYB, which in turn upregulates IL-1β, CXCL2 and CCL20. HCC-derived cytokine transforms macrophages to the M2 phenotype to foster an inhibitory tumor microenvironment and anti-PDL1 tolerance. Importantly, LINC01137 transcription is activated by the NFYB/KAT2B complex in a feed-forward loop. Notably, treatment with an IL-1β inhibitor enhances the blockade efficacy of PD-L1 in NFYB-overexpressing HCC. Our findings imply an immunosuppressive role of NFYB-LINC01137 signaling during aggressive HCC progression and support the concept of microenvironment engineering in immunotherapy.

Throughout history, herbal medicines and natural products have played a crucial role as therapeutics for humans, yet their molecular mechanisms of action often remain elusive. Here, we investigate whether primulagenin A (PGA) from the traditionally used herbal substance Primula root acts via the nuclear receptor RORγ, a key regulator of pro-inflammatory Th17 cells, which are linked to autoimmune diseases like psoriasis. Full-length luciferase assays revealed a high potency (IC₅₀ = 119 nmol/L) and efficacy (Imax = 87%) of PGA as an inverse agonist of RORγ. To ensure sufficient supply, we established methods to isolate and synthesize PGA. Its binding to the human RORγ ligand binding domain was confirmed by nano differential scanning fluorimetry, and a structure-activity relationship was proposed by docking and site-directed mutagenesis. qPCR revealed PGA-mediated downregulation of RORγ target gene expression. Furthermore, PGA inhibited murine and human Th17 differentiation in a concentration-dependent manner and reduced the proportion of IL-17A-producing Th17 cells, as assessed by flow cytometry. In this work, we identify PGA as a new, potent, and efficacious inverse agonist of RORγ, with potential for modulating immune responses in inflammatory and autoimmune diseases.

Kinase inhibitors targeting FLT3-ITD, such as Gilteritinib, have emerged as promising targeted therapies. However, recent clinical trials have shown disappointing overall survival (OS) outcomes in acute myeloid leukemia (AML) patients, primarily due to disease recurrence following treatment. We uncovered a potential mechanism underlying Gilteritinib resistance. Gilteritinib treatment induced reprogramming of lactic acid metabolism in AML cells, leading to increased H3K27 lactylation that continuously amplified c-KIT expression and signaling in AML cells. This mechanism enriched leukemia stem cells (LSCs), driving drug resistance and disease relapse. Notably, c-KIT kinase inhibitors failed to effectively counteract the progression of relapsed and refractory AML, as c-KIT overexpression results in amplification of its signaling. To address this issue, a dual degrader targeting both FLT3-ITD and c-KIT was identified. Beyond exhibiting stronger efficacy than Gilteritinib in inhibiting AML cell proliferation, this PROTAC also demonstrates a significant ability to induce cell differentiation. In cell line-derived xenograft (CDX) models, the degrader significantly suppressed FLT3-ITD⁺ AML recurrence and prolonged the survival of experimental mice. Furthermore, in PDX model established using AML cells from Gilteritinib-resistant patients, the degrader showed significantly superior therapeutic efficacy compared to the combination treatment of Gilteritinib and Imatinib. As a candidate drug molecule, this degrader exhibits promising potential for clinical translation.

Targeting host factors critical to the viral life cycle instead of direct viral enzyme inhibition represents a promising alternative strategy for developing broad-spectrum antivirals. Here, we identified VPS34, a key regulator of autophagosome-lysosome fusion and membrane trafficking, as a conserved host-dependency factor across coronaviruses. VPS34 gene knockdown significantly attenuates viral replication both in vitro and in vivo. Crucially, this antiviral effect remained potent against emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, demonstrating that VPS34 is a drug target resilient to viral evolution. Based on the scaffold structure of the VPS34 inhibitor SAR405, we developed YBM, a novel small-molecule inhibitor, via critical group substitutions and aliphatic chain introduction. YBM exhibited superior pharmacokinetic properties than SAR405, including enhanced bioavailability and prolonged plasma half-life. YBM shows significant in vivo efficacy against SARS-CoV-2 and HCoV-OC43. Crucially, its broad-spectrum potential is underscored by potent in vitro activity against multiple coronavirus genera (α and γ). This study established YBM as a host-targeting antiviral (HTA) that targets VPS34, offering protection against both extant and evolving coronaviruses. The evolutionarily conserved role of VPS34 in mediating coronavirus replication suggests that this host factor may become a priority therapeutic target for coronaviruses during future pandemics.

TGR5 and FXR are key regulators of metabolic homeostasis and cardiovascular health. Since the cardioprotective capacity of TGR5 activation and FXR inhibition has been recognized, dual modulation of these targets offers a promising therapeutic strategy for myocardial ischemia/reperfusion injury. Herein, sulfonyl benzoic acid derivatives were identified as effective bidirectional modulators, with compound E6 emerging as a potent lead compound. E6 demonstrated robust dual-target activity, significantly preserving cardiomyocyte viability and attenuated reactive oxygen specie overproduction in hypoxia/reoxygenation models. Moreover, oral administration of E6 markedly reduced infarct size and improved cardiac contractile function after ischemia/reperfusion in vivo, without inducing gallbladder-related side effects. Notably, E6 demonstrated superior efficacy in restoring systolic function compared to mono-regulators. Transcriptomic analysis and subsequent validation studies suggested that its therapeutic effects are mediated through favorable modulation of inflammatory response, attenuation of apoptosis, and enhanced cardiomyocytes survival. Our findings underscore the therapeutic advantages of dual TGR5/FXR targeting and establish E6 as a promising bifunctional lead compound for the treatment of myocardial ischemia/reperfusion injury.

Compared with conventional cataplasms, those incorporating a cross-linked network structure significantly enhance their mechanical strength and cohesion, endowing them with good formability and adhesion properties, solving problems such as cold flow and slippage, thereby greatly increasing the convenience of use. However, systematic studies investigating the structural profiling of cross-linked networks in cataplasms remain scarce, limiting a comprehensive understanding of their functional significance. Therefore, we developed a systematic methodology to characterize emulsion-type cataplasms (as a model formulation) with cross-linked network structures, classifying their key structural parameters into four levels. The primary structures defined formability and adhesion, ensuring intact and durable skin adhesion. The secondary structure was intermediates formed by the drug and oily components. The tertiary structure was a dynamic structure, evaluating the quality changes of cataplasms during processes such as crosslinking and storage. The quaternary structure was a molecular structure, representing the mechanism by which the cross-linked network structure was formed. The factors influencing structural parameters and the laws between the intrinsic structures were investigated. Furthermore, we established threshold values for the primary structures, indicating when cataplasms possess optimal formability. This study offers new insights for cataplasm design and provides valuable references for industrial development.

Platelets play a critical role in tumor development, metastasis and chemoresistance, making the effective killing of tumor cells and simultaneously targeted disruption of platelet functions essential for improving cancer treatment outcomes, especially in post-surgical malignant tumor patients. Here, we develop soft hybrid microparticles (3D-PMPs) by fusing tumor-repopulating cell-derived microparticles with inactivated platelet membranes to deliver the anticancer agent doxorubicin (DOX@3D-PMPs). Leveraging their unique softness, DOX@3D-PMPs demonstrate superior tumor accumulation, deep tumor penetration, and enhanced internalization into tumor cells, leading to efficient tumor cell killing. Additionally, 3D-PMPs function as highly targeted platelet decoys to disrupt platelet-tumor cell interaction and reduce platelet-driven tumor proliferation and metastasis. Mechanistically, Toll-like receptor 4 (TLR-4) presented on 3D-PMPs is responsible for their platelet decoy function. DOX@3D-PMPs demonstrate significantly enhanced therapeutic efficacy in both orthotopic 4T1 breast tumors and post-surgical orthotopic 4T1 breast tumors. This work offers a novel and effective approach to enhance the therapeutic outcomes in cancer treatment, particularly in post-surgical settings.

Local inhibition of the “patching” function of tumor-associated platelets against neutrophil infiltration-caused vascular breaches has been used as an “enhanced permeability and retention (EPR) amplification” strategy. Nevertheless, the vascular leakage-resulted elevation of interstitial fluid pressure (IFP) could impact tumoral perfusion and convection of nanodrugs. Especially for hypoperfused and desmoplastic pancreatic ductal adenocarcinoma (PDAC), solely relying on vascular destruction would predictably diminish tumoral drug perfusion. According to multi-thrombosis formation in PDAC, a microthrombi and matrix co-targeted dasatinib (DAS) nano-micelle (CPHD/DAS) synchronizing endothelial gap opening and matrix decompression was constructed for sustained augmentation of drug perfusion within PDAC. CPHD/DAS was composed of CREKA peptide-modified hyaluronic acid-deoxycholate conjugates co-assembled with DAS. In vitro and in vivo results demonstrated CPHD/DAS not only retarded tumor-associated platelet activation to enhance vascular permeability and expose subvascular matrix, but also inhibited pancreatic stellate cell activation to alleviate stroma barrier. Thus, the matrix decompression resisted IFP elevation caused by endothelial gap opening, facilitating sustained up-regulation of functional vessels. Based on superior tumor accumulation and penetration, CPHD/DAS exhibited favorable potency in Panc02 tumor model. This study provides a paradigm to improve the efficiency and application scope of “EPR amplification” strategy in antitumor therapy.

Dendritic cell (DC) vaccines represent a promising immunotherapeutic strategy by eliciting potent anti-tumor immunity. However, their clinical application remains limited due to poor lymph node (LN) targeting and inadequate T cell activation. Here, we developed an LN-targeted cell-nanoadjuvant conjugate by click-chemistry conjugation of anti-PD-1 antibodies (αPD-1) and Resiquimod (R848) liposomes to DC vaccines (DCVs) (DCV-αPD-1/Lipo) to enhance DC-T cell crosstalk for cancer immunotherapy. DCV-αPD-1/Lipo maintains higher co-stimulatory molecule expression and antigen presentation with enhanced LN targeting efficiency than conventional DC vaccines. The surface-conjugated αPD-1 increases DC-T cell adhesion by 4.97-fold while amplifying the IFN-γ/IL-12 positive feedback loop, thereby potentiating T cell activity and augmenting effector T cells and other immune cells mediated anti-tumor efficacy. This multifunctional integration of adaptive DC therapy, nanoadjuvants and checkpoint blockade establishes an effective approach for next-generation DC therapy.

The immunosuppressive tumor microenvironment (TME) profoundly limits the therapeutic efficacy of CD8⁺ T cells in solid tumors. While cytokine therapies have shown promise in reactivating CD8⁺ T cells, they fail to address the common suppressive environmental attributes (e.g., acidosis and Mg²⁺ deficiency) of solid tumors. Here, we report an innovative CD8⁺ T cell dual-functional modulator, interleukin-12-tethered nano-aluminum adjuvant (IL12@NAM), which counteracts the acidic TME to relieve acidosis and concurrently releases Mg²⁺ and IL12. Locally released Mg²⁺ and IL12 synergize in T cell infiltration and activation by promoting the phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, and enhance CD8⁺ T cell activation and functions via the Ca²⁺-nuclear factor of activated T cells 2 pathway. Furthermore, dual-functional IL12@NAM mitigates CD8⁺ T cell exhaustion by reducing PD1 and LAG3 expression and effectively increases the differentiation towards T helper 1 cells while decreasing regulatory T cells, creating a more favorable immune network for enhanced CD8⁺ T cell-mediated anti-tumor immunity. As a result, IL12@NAM has demonstrated potent therapeutic efficacy against advanced melanoma and breast cancer, and remarkably empowered adoptive T therapy of solid tumors. This study provides a paradigm for empowering cytotoxic T cells by reactivating and creating a sustainable immunoresponsive environment, offering a potential adjuvant strategy to enhance solid tumor therapy.

Poly (ADP-ribose) polymerase (PARP) inhibitors though effective in patients with homologous recombination (HR)-deficient tumors, a large population of patients remain unresponsive, primarily due to either the absence of HR-related mutation or the restoration of HR functionality. RAD51, a critical protein in HR repair signaling that ensures precise DNA lesion repair, represents a promising therapeutic target. Inspired by the clinical success of PARP inhibitors in treating BRCA1/2-mutant cancers and leveraging the potential of proteolysis-targeting chimeras (PROTAC) technology—a method that exploits the cell's protein degradation machinery to eliminate disease-associated proteins, we generated a small-molecule PROTAC G73. This compound degrades RAD51 in a concentration- and time-dependent manner, effectively mimicking the HR-deficient phenotype by impairing DNA double-strand break (DSB) repair. Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.

Microorganisms can activate anti-tumor immune responses via the innate immune system. However, this immune effect lacks specificity, and prolonged stimulation by live bacterial colonization may lead to immune tolerance. Sonodynamic therapy triggers cellular death and lysis, fully activating the antigen presentation process by providing heterologous DNA and tumor antigen in situ. Herein, to enhance the immunological effect facilitated by ultrasonic treatment, a manganese-containing porphyrin-based metal-organic framework (Mn-MOF) was modified as an acoustic sensitizer on the surface of Escherichia coli to form bacterial sonosensitizer hybrid systems (HA@Mn-MOF@E). Importantly, HA@Mn-MOF@E was able to target and colonize 4T1 tumors due to the anoxic tendency of anaerobes. The ultrasound-induced bacterial and tumor cell death and released manganese could activate macrophages and dendritic cells (DCs) through the activation of the cGAS-STING pathway, which increased the proportion of CD3⁺ T cells and M1/M2 ratio within the tumor, as well as CD8⁺ effector T cells and CD86⁺ DCs in lymph nodes. By sono-sensitized immunotherapy, HA@Mn-MOF@E was demonstrated to inhibit orthotopic 4T1 tumor progression and induce tumor necrosis effectively. Such a designed bacterial sonosensitizer hybrid system offered the possibility of using sonodynamic assistance to sensitize live microorganisms-induced immunotherapy, with thorough activation of the antigen presentation in the tumor.

Platinum-based chemotherapy only achieves a short-term success in the treatment of triple-negative breast cancer (TNBC), which is attributed to immunosuppressive macrophages post-chemotherapy. Herein, inspired by the plant immune defense mechanism, we demonstrate that edible astragalus-derived exosome-like nanoparticles (ADNPs) exhibit conspicuous efficacy in reprogramming M1-like tumor-associated macrophages (TAMs) through the activation of TLR2 signaling. The docking between released formononetin and TLR2 plays a key role during the cell internalization process. As a result, ADNPs in combination with Cisplatin (termed ADNP-Cis) greatly inhibit TNBC murine tumor progression and metastasis. Besides, ADNPs alleviate the peripheral blood toxicity caused by cisplatin treatment, and show lower toxicity compared with other TLR2 agonists previously reported. Taken together, this safe and robust ADNP-Cis therapy offers fresh insights into the management of TNBC chemotherapy.

Pterocarpans and isoflavans are important phytoalexins, and demonstrate significant benefits to human health. Pterocarpan reductases (PTRs) catalyze the conversion of pterocarpans to isoflavans, while the catalytic mechanism remains unknown. Herein, we report six PTRs (GuPTR1-6) from Glycyrrhiza uralensis, together with the first PTR crystal structure (GuPTR1/(-)-medicarpin/NADP⁺, 1.8 Å). Structural analysis and mutagenesis reveal that a lysine-mediated deprotonation of the 7-OH group triggers C‒O bond cleavage of pterocarpans in the furan ring-opening reactions. This mechanism also applies to similar ring-opening enzymatic reactions. Through ancestral sequence reconstruction, we obtained a multifunctional reductase N0, which could accept different types of 4-(furan-2-yl) phenol derivatives as substrates. This study not only unveils the catalytic mechanisms of PTRs, but also provides a powerful enzymatic tool for the synthesis of bioactive isoflavans.

RNA viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses, and alphaviruses, represent a major source of emerging human infectious diseases. They pose a persistent threat to public health; however, few therapeutic options are available for severe infections. Through a natural product screening campaign, we identified ansatrienin B as a broad-spectrum inhibitor of multiple RNA viruses, including SARS-CoV-2, flaviviruses (e.g., YFV, WNV, DENV), and alphaviruses (e.g., CHIKV). Time-of-drug-addition assays indicated that ansatrienin B acts at both the early (entry) and intermediate (replication) stages of the viral life cycle. Surface plasmon resonance (SPR) and molecular docking studies validated a direct interaction between ansatrienin B and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and WNV. Combined RNA pull-down and RdRp enzymatic activity assays (in gel, solution, and cellular forms) further demonstrated that ansatrienin B disrupts both the binding of RdRp to viral RNA and its enzymatic activity. In vivo, ansatrienin B showed significant efficacy in mouse models infected with SARS-CoV-2 or WNV infection. To facilitate screening and elucidate the structure-activity relationship (SAR), we generated a focused ansatrienin library via a mutasynthetic approach. Supplementation of four 3,5-AHBA analogs into a △mycB1-B4 mutant strain of Streptomyces flaveolus yielded 30 novel ansatrienin derivatives. Evaluation of anti-SARS-CoV-2 activity identified four analogs with enhanced potency, enabling the establishment of a preliminary SAR. Collectively, these findings establish ansatrienin B as a novel inhibitor targeting RdRp and provide a foundation for the development alternative broad-spectrum antiviral agents.