During early embryogenesis, epiblast cells ingress through the primitive streak (PS) to adopt a mesendoderm (MES) fate, giving rise to both mesodermal and endodermal lineages. Robust systems that accurately recapitulate MES specification—and thereby enable a comprehensive understanding of cell fate transitions during PS formation—remain limited. Here, we describe 3-dimensional MES organoids derived from human induced pluripotent stem cells that faithfully model in vivo human MES specification, particularly from the anterior PS. MES specification requires PTEN expression, as PTEN loss profoundly impairs mesoderm and definitive endoderm derivatives. Integrative multi-omics analyses—including transcriptomics, chromatin accessibility, metabolomics, and phosphoproteomics—on wild-type and PTEN^−/− MES cells revealed that PTEN suppresses retinoic acid (RA) signaling during MES commitment. Furthermore, we identified the RA-degrading enzyme CYP26A1 as a downstream effector of PTEN. Notably, while excessive RA induced by PTEN ablation is detrimental to MES cell generation, physiological levels of RA are necessary. Collectively, the human MES organoids offer a valuable model for dissecting early human development, and our findings identify PTEN as a key regulator of MES fate commitment through inhibition of RA signaling.

Precision theranostics for castration-resistant prostate cancer remain a major challenge because of tumor heterogeneity, drug toxicity, and resistance to conventional therapies. Here, we report a multifunctional theranostic nanoplatform that integrates multimodal imaging guidance, dual-targeted delivery, photothermal therapy, and immune activation for the precision treatment of prostate cancer. By encapsulating aggregation-induced emission luminogens and magnetic nanoparticles, this system achieves superior second near-infrared fluorescence and magnetic resonance imaging fusion for deep-tissue visualization. The dual-targeting strategy, which integrates magnetic navigation with simultaneous engagement of six-transmembrane epithelial antigen of the prostate 1 and prostate specific membrane antigen (PSMA), effectively addresses tumor heterogeneity by enabling externally guided and biologically specific delivery to both PSMA⁺ and PSMA⁻ prostate cancer cells. Upon targeted delivery, the synergistic combination of photothermal therapy and chemotherapy achieves potent tumor growth inhibition, activates CD8⁺ T cells and macrophages to promote robust antitumor immune responses, and elicits durable immunological memory to prevent tumor recurrence. In vitro and in vivo studies demonstrate superior tumor targeting specificity, enhanced imaging contrast, and minimal off-target toxicity. This study provides novel insights into the construction of a multifunctional theranostic nanoplatform in precision oncology, with promising translational potential for clinical management of castration-resistant prostate cancer.

Plant-derived extracellular vesicles are promising candidates for oral drug delivery, yet their clinical translation is hindered by limited targeting precision and inconsistent systemic absorption. While surface engineering can enhance tissue accumulation, strategies that preserve biocompatibility and enable scalable production remain limited. Here, we introduce boiling as a simple thermal processing approach that structurally reconfigures ginger extracellular vesicles (GEVs) into functionally enhanced, thermally reassembled GEVs (T-GEVs). The surface architecture of T-GEVs is enriched with key vesicle trafficking regulators, including V-type proton adenosine triphosphatase subunit G, ARF1, and β-adaptin-like protein. This specific composition drives their tissue-specific accumulation in the intestine and liver and potentiates clathrin-dependent cellular uptake in intestinal cells by 8.57-fold. Beyond superior intrinsic anti-inflammatory activity through NLRP3 inflammasome suppression, T-GEVs function as an efficient oral delivery platform. When loaded with tumor necrosis factor-α (TNF-α) small interfering RNA, they enable a synergistic therapy that combines innate anti-inflammatory activity with targeted gene silencing of TNF-α, showing potent efficacy in colitis. Our findings position boiling as a natural strategy for enhancing the bioactivity and targeted oral delivery potential of GEVs.

Cell-based therapeutics hold immense promise for clinical intervention, yet their practical translation is severely bottlenecked by suboptimal delivery kinetics, safety risks, and low patient adherence. This review provides a comprehensive overview of recent innovations in microneedle (MN)-based cell delivery systems and their applications across multiple organs. We initiate the discussion by evaluating progress in regenerative medicine, specifically targeting stem and immune-derived lineages. The article further classifies MN systems for cell therapy delivery according to material composition, fabrication techniques, and functional characteristics, with an in-depth discussion of innovative designs, highlighting their unique advantages. Additionally, we categorize and analyze recent studies on MN-based cell therapy for skin diseases, endometrial repair, cardiac regeneration, and oral disorders. Beyond summarizing current achievements, we critically examine the translational barriers that limit clinical adoption, including manufacturing scalability, storage stability, and regulatory considerations. This review provides a systematic and organ-specific overview that may help guide the design of improved and more clinically translatable cell delivery platforms.

Cancer-related lymphedema is a chronic progressive side effect of cancer treatments followed by lymph node dissection or radiotherapy. Clinicians often identify lymphedema through limb swelling, while the disease begins earlier than that. Lymphatic injury is the original cause, where elevated interstitial fluid pressure and distorted tissue mechanics will lead to immune activation and fibrofatty remodeling. Recently, mechanobiology studies have deepened our understanding by linking lymph stasis to T helper 2/transforming growth factor β signaling, fibroblast mechanotransduction, and YAP/TAZ activity that together lock tissues into a stiff, poorly draining state. Simultaneously, emerging artificial intelligence (AI) in the field are being explored, from proof-of-concept image classification to much more diagnostic models that integrate elastography, indocyanine green lymphography, radiomics, clinical variables, and wearable signals to detect preclinical mechanical signatures and predict risk. These advances are driving the development of promising mechanomedical approaches, such as adaptive compression systems, AI-assisted plans for lymphatic reconstruction, anti-fibrotic strategies, and lymphangiogenic regeneration, although most remain at preclinical or early clinical feasibility stages of translation. We discuss the strength of current evidence, challenges for clinical translation, and standards for reporting. We propose that cancer-related lymphedema can be understood as a measurable and targetable mechano-immune-fibrotic disease, for which AI may eventually support earlier diagnosis, risk prediction, and personalized mechanotherapy.

Spinal cord injury often causes permanent disability because the body’s own repair mechanisms are limited, and the molecules that control damage and healing are not fully understood. One such molecule, FK506-binding protein 5 (FKBP5), is known to rise sharply after injury, but whether it only drives harmful inflammation or also participates in later recovery has been unclear. In this study, we investigated how FKBP5 affects microglia—the brain’s immune cells—at different stages after spinal cord injury in mice. We found that FKBP5 plays a dual role. In the first few days, it works together with another protein, GPR84, to boost the production of an inflammatory signal called interleukin-1β. This signal pushes microglia into a destructive state and triggers a coordinated form of neuronal cell death that involves multiple death pathways. However, as FKBP5 levels continue to rise over time, it switches its function. It binds to and modifies an enzyme called LDHA, changing how microglia process lactate. This lactate then acts as a signal to add chemical tags (lactylation) onto histones, which turns on a protective gene, Fxyd5, and its partner Lgals1. These changes convert microglia from a harmful to a healing state, reduce neuronal death, and improve the local environment for tissue repair. Our results reveal that FKBP5 is a double-edged sword—first worsening damage, then promoting repair. This discovery suggests that precisely timing therapies that target FKBP5 could offer a new way to improve recovery after spinal cord injury.

Uterine fibroids pose a major global health burden, affecting approximately 120 million women worldwide. While minimally invasive surgeries, such as electromechanical morcellation, preserve fertility, they are severely hampered by the risk of unpredictable tissue dissemination—a hazard that prompted a U.S. Food and Drug Administration black-box warning. Resolving this clinical dilemma requires a paradigm shift in instrument design. This review identifies a persistent “mechanical blind spot”: Current surgical tools operate with static parameters that fundamentally clash with the profound multi-scale mechanical heterogeneity of fibroids. Driven by FIGO-defined microenvironments and degeneration-driven remodeling, this extreme variability in tissue stiffness shapes the dynamic—and often hazardous—cutting challenges during surgery. To bridge this critical gap, we review the mechanobiological origins of this heterogeneity and analyze its direct impact on morcellation-induced fragmentation. We then synthesize multiscale mechanical quantification methods (ex vivo and in vivo) and evaluate the evolution of instrument-optimization strategies. Moving beyond conventional structural refinements, we highlight the potential of bio-inspired end-effectors for safe tissue interaction. Crucially, we propose a technological roadmap integrating these physical mechanisms with artificial intelligence—enabling preoperative “mechanical mapping” and real-time adaptive control. Taken together, this work offers new perspectives for the clinical management of this prevalent condition and provides a comprehensive theoretical framework for developing next-generation, mechanics-aware surgical ecosystems.

Diabetic kidney disease, the leading cause of end-stage kidney disease worldwide, involves complex interactions beyond classical hemodynamic and oxidative stress pathways. Recent advances emphasize metabolic reprogramming in renal cells—characterized by mitochondrial dysfunction, impaired fatty acid oxidation, lipotoxicity, and glycolytic shifts—as upstream drivers of cellular injury and fibrosis. Single-cell RNA sequencing reveals profound immunometabolic heterogeneity, including dynamic macrophage subpopulations (e.g., proinflammatory early states transitioning to TREM2^hi/MRC1^hi lipid-associated phenotypes) and T helper 17/regulatory T imbalance, which amplify inflammation via bidirectional crosstalk with podocytes, tubular cells, and mesangial cells. Interorgan axes, particularly gut dysbiosis and uremic toxin accumulation, further perpetuate immune dysregulation. This review integrates these insights to propose precision strategies targeting mitochondrial homeostasis, ferroptosis inhibition, glycolytic blockade in immune cells, and multimodal therapies (e.g., combination strategies integrating sodium–glucose cotransporter 2 inhibitors with immunometabolic modulators). Multi-omics integration and spatial transcriptomics hold promise for individualized and mechanism-guided interventions to halt diabetic kidney disease progression.

Colorectal cancer (CRC) remains a global health challenge with rising incidence in younger populations and limited efficacy of current chemotherapies. In this study, we investigated the anti-tumor mechanisms of metochalcone (MET), a natural chalcone derivative, in CRC. Using a combination of transcriptomic, proteomic, and targeted in vitro and in vivo assays, we found that MET substantially reduced viability, migration, and invasion and arrested the cell cycle at the G₀/G₁ phase in HCT-116 CRC cells. Integrative analysis identified heme oxygenase-1 (HO-1) as a key target, and molecular docking and cellular thermal shift assay confirmed that MET directly binds to and stabilizes the HO-1 protein. Mechanistically, MET treatment led to mitochondrial dysfunction, characterized by increased reactive oxygen species and decreased membrane potential, which in turn activated PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy. In 2 distinct mouse models of CRC, MET potently suppressed tumor growth. Furthermore, 16S ribosomal RNA gene sequencing revealed that MET treatment was associated with changes in gut microbiota composition in mice, including an increased relative abundance of beneficial Lactobacillus and a decreased abundance of pro-inflammatory Desulfovibrionaceae. Our findings demonstrate that MET exerts multifaceted anti-tumor effects, including direct targeting of HO-1 and activation of PINK1/Parkin-mediated mitophagy, accompanied by alterations in gut microbiota composition.