While glucose-lipid metabolic remodeling is recognized as a major contributor to cardiomyocytes proliferation, the role of amino acid metabolism in cardiac regeneration remains poorly understood. In this study, glycine was identified as a previously unrecognized pro-proliferative amino acid. Primary cardiomyocytes, neonatal mice, and adult mouse models of myocardial infarction were employed to investigate the pro-proliferative effects of glycine on cardiomyocytes. Cardiomyocyte proliferation was assessed by immunofluorescence staining of cell-cycle-related markers. Cardiac function was evaluated by echocardiography, and histopathological alterations were examined using Masson's trichrome staining. To overcome the pharmacokinetic limitations of free glycine and enhance therapeutic efficacy, a cardiac-targeted liposomal nanoformulation (LNP@Gly) was developed and applied in vivo. Mechanistic studies were performed using RNA sequencing, Western blotting, co-immunoprecipitation (co-IP), immunostaining, pharmacological inhibition and activation approaches. Exogenous glycine supplementation (700 mg/kg) consistently enhanced cardiomyocyte proliferation across in vitro, neonatal, and adult myocardial infarction models. In infarcted adult hearts, glycine supplementation further improved cardiac function and reduced myocardial fibrosis. A cardiac-targeted liposomal formulation of glycine (LNP@Gly) effectively overcame the pharmacokinetic limitations of free glycine and achieved enhanced therapeutic efficacy at a substantially lower dose (4 mg/kg). At the molecular level, glycine treatment was associated with increased AKT phosphorylation, reduced GCN2 activation, and weakened GCN2-AKT interaction. Pharmacological modulation further supported a critical role for the GCN2-AKT axis in glycine-induced cardiomyocyte proliferation and cardiac repair. These findings identify glycine as a novel metabolic regulator of cardiomyocyte proliferation and cardiac regeneration through modulation of the GCN2-AKT signaling axis. Moreover, the integration of amino acid-specific metabolic regulation with cardiac-targeted nanodelivery represents a translatable therapeutic strategy for ischemic heart disease.

Endometrial regeneration remains a significant clinical challenge for women with intrauterine adhesions (IUAs), thin endometrium, or uterine factor infertility, conditions that severely impair fertility and reproductive outcomes. Traditional hormonal and surgical interventions often fail to restore the structural and functional integrity of damaged endometrial tissue. This review comprehensively examines integrative bioengineering strategies for endometrial regeneration, focusing on the synergistic applications of biomaterials, stem cells, organoids, and organ-on-a-chip technologies. Natural polymers such as collagen, gelatin, alginate, hyaluronic acid, and synthetic polymers including PCL, PLA, PGA, and PLGA have been comprehensively evaluated for their ability to mimic extracellular matrix, support cell proliferation, angiogenesis, and modulate immune responses. The incorporation of mesenchymal stem cells, extracellular vesicles, and growth factors into bioengineered scaffolds, such as hydrogels and nanofiber membranes, enhances regenerative efficacy. Furthermore, emerging platforms, such as endometrial organoids, 3D bioprinting, and organ-on-a-chip systems, offer physiologically relevant models for precision regenerative medicine. Innovations such as AI-assisted monitoring, 4D printing, and advanced drug delivery systems represent transformative approaches to overcome current therapeutic limitations. This review highlights the convergence of materials science, stem cell biology, and microengineering as a foundation for next-generation, personalized therapies aimed at restoring endometrial function and fertility. In addition, the review highlights biomaterial-based strategies as the foundation of endometrial regeneration, by detailing how natural polymers (e.g., collagen, gelatin, alginate, hyaluronic acid) and synthetic polymers (e.g., PCL, PLA, PLGA) support tissue repair structurally and by mediating biological functions. The integration of advanced technologies, such as 4D printing, AI-assisted monitoring, and stem cell-derived extracellular vesicle delivery has emerged as a transformative direction for overcoming current clinical challenges. Collectively, these approaches offer a next-generation therapeutic paradigm for restoring endometrial function and fertility.

The Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9 (CRISPR-Cas9) endonuclease system has revolutionized biology research by enabling precise, efficient, and versatile genome editing. However, achieving spatiotemporally controlled gene editing within specific organs, tissues, or cells remains a major challenge, as unregulated CRISPR-Cas9 activity can lead to severe off-target effects, hindering its clinical translation. To enhance the on-target precision and reduce the unwanted consequences of aberrant or premature CRISPR-Cas9 activation, various strategies have been developed to regulate its function at translational or post-translational stages using diverse external physicochemical stimuli. While chemical molecule-inducible CRISPR-Cas9 systems have demonstrated significant progress, most of them still suffer from inherent deficiencies, such as unsatisfactory spatiotemporal precision, irreversibility, pharmacokinetic dependence, internal disturbance, and safety concerns related to chemical inducers. By contrast, externally applied physical stimuli provide distinct advantages for triggering CRISPR-Cas9 activity, offering superior spatiotemporal precision, reversibility, and biocompatibility. These features significantly enhance the controllability, target specificity, and practical applicability of CRISPR-Cas9 systems across diverse biological settings. This review systematically explores recent advances in physical stimuli-responsive CRISPR-Cas9 platforms, detailing their design strategies, activation mechanisms, and proof-of-concept applications. Furthermore, we provide a comparative analysis of different stimulation strategies, highlighting their respective characteristics, current limitations, and future prospects. A discussion on the persistent bench-to-bedside gap is also included, aiming to guide future development toward clinically viable solutions.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal clinical outcomes. We identified hsa_circ_0058495 as significantly upregulated in PDAC tissues and PDAC cell-derived exosomes, where it contributes to tumor proliferation and invasion. The molecular mechanisms underlying its oncogenic function, however, remain incompletely understood.Methods: Differential circRNA expression was profiled by RNA sequencing. The functional role of hsa_circ_0058495 and its molecular interactions were interrogated through Western blotting, RT-qPCR, co-immunoprecipitation, RNA pull-down, and RNA immunoprecipitation assays. Confocal microscopy and PET/CT imaging were employed to delineate its biological effects in vitro and in vivo.Results: Hsa_circ_0058495 was enriched in PDAC-derived exosomes and stabilized IGF2BP2 by preventing TRIM25-mediated ubiquitination and attenuating autophagy-dependent degradation. Stabilized IGF2BP2 enhanced the stability of MEKK1 mRNA, leading to sustained ERK1/2 phosphorylation and consequent promotion of PDAC cell proliferation and invasion. Moreover, exosomal hsa_circ_0058495 facilitated M2 macrophage polarization, thereby fostering an immunosuppressive tumor microenvironment.Conclusions: Hsa_circ_0058495 promotes PDAC progression by stabilizing IGF2BP2 and activating the MEKK1-ERK signaling cascade, while exosomal transfer of hsa_circ_0058495 drives M2 macrophage polarization to reinforce tumor-associated immunosuppression. These findings establish hsa_circ_0058495 as a pivotal regulator of PDAC progression and underscore its potential utility as both a diagnostic biomarker and a therapeutic target.

Background: Excessive oxidative stress activation in diabetic chronic wounds causes ongoing inflammation and cell dysfunction, which greatly impairs healing. Heterojunction photocatalytic nanozymes can potentially scavenge reactive oxygen species (ROS), but their clinical application faces challenges due to low photocatalytic efficiency, poor biocompatibility, and limited stability in physiological environments.Methods: APTES-COF-1@MXene heterojunction nanozymes (AC-1@MXene) were synthesized using chemical methods combined with in-situ growth techniques. Double-layered hydrogel microneedle systems (ACMGM) were fabricated through UV polymerization with tips loaded with AC-1@MXene. The photocatalytic performance of the nanozymes was assessed using physicochemical methods. Biocompatibility was confirmed through biochemical assays, and the therapeutic effectiveness of ACMGM was evaluated in diabetic mouse wound models.Results: AC-1@MXene multifunctional photocatalytic nanozymes were successfully developed, exhibiting both catalase and superoxide dismutase activities. These nanozymes demonstrated significantly enhanced enzymatic activity under visible light, efficiently converting H2O2 and ·O2- into H2O and O2, thus providing strong antioxidant protection. In vitro tests confirmed excellent biocompatibility, while in vivo studies showed that ACMGM microneedles effectively facilitated transdermal delivery of nanozymes. This significantly aided diabetic wound healing and reduced local oxidative stress. Mechanistic insights revealed that tissue regeneration and repair resulted from synergistic effects, including anti-inflammatory actions, M2 macrophage polarization, angiogenesis, and increased collagen synthesis.Conclusion: The ACMGM microneedle system effectively delivers nanozymes through the skin and enhances their catalytic activity upon exposure to visible light. This precisely modulates the oxidative stress microenvironment in refractory wounds, offering an innovative therapeutic strategy for diabetic wound treatment.

Background: Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED.Methods: We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism.Results: Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. In vivo, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling.Conclusions: Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.

Rationale: The mode of action of [177Lu]Lu-PSMA-617 (LuPSMA) therapy is not fully understood and a relevant fraction of patients show treatment failure. Therefore, this study aimed to investigate the prognostic significance of immune suppression in the tumor immune microenvironment (TME) of LuPSMA therapy patients.Methods: Tumor tissue samples from 61 patients, who were referred for LuPSMA from March 2018 until March 2022, were retrieved. Among these, 40 patients fulfilled all criteria and were therefore included in the analysis. Of these, 3 patients had two biopsies; prior and under systemic treatment, which is why we analyzed 43 samples: 29 (67%) with treatment-naïve tissues samples (cohort 1) and 14 (33%) during systemic treatment. Patients were followed up to assess overall survival. We examined gene expression and immune cell counts (derived from gene expression data) in the two sub-cohorts through transcriptome profiling with the Decipher prostate assay (Veracyte, San Diego, CA), a subset of these patients has been described previously.Results: In the total cohort, the ratio of activated (M1)/naive (M0) macrophages (HR = 0.90 [0.84-0.98]; p = 0.009) was a significant prognosticator of OS. In cohort 1, PD-L2 expression (HR = 1.07 [1.02 - 1.11]; p = 0.003)) and the M1/M0 ratio signature (HR = 0.89 [0.81-0.99]; p = 0.026) were significant independent prognostic factors of OS when analyzed together in a multivariate analysis. AR gene expression was significantly elevated in cohort 2 compared to 1 (p < 0.001). Several DNA repair signatures analyzed were significantly higher in cohort 2 than in cohort 1 (p < 0.05). In cohort 2, PD-L2 expression (HR = 0.87 [0.77 - 0.98]; p = 0.017) emerged as an independent prognostic factor associated with improved OS when included in a multivariate model with the immune 190 score, a negative prognosticator in this analysis (HR = 1.25 [1.02 - 1.53]; p = 0.028).Conclusions: The ratio of M1/M0 macrophages was associated with favorable outcome of LuPSMA in the total cohort of patients. In treatment-naive patient samples, PD-L2 expression was associated with unfavorable, whereas M1/M0 macrophages with favorable outcomes, which might indicate that immune checkpoint inhibition could be a combination partner of LuPSMA therapy. In patient biopsy samples acquired after the start of systemic treatment, AR gene expression and DNA repair signatures appear to be significantly altered and PD-L2 became a protective marker.

Radiotherapy is one of the most commonly prescribed anticancer modalities in the clinic, which is widely recognized as an effective and safe treatment for a broad spectrum of solid tumor indications. Interestingly, there is increasing evidence that the tumors can dynamically modulate cell fate decisions after ionizing radiation (IR) exposure, which is beneficial for escaping the radiation-induced antitumorigenic cell damaging and immunostimulatory impacts. Consequently, the regulatory network of cell fate determination could be a promising target for enhancing the susceptibility of tumor cells to various radiotherapeutic modalities. In this review, we provide a comprehensive account on the mechanisms of post-radiation cell fate control in tumor cells to escape programmed cell death (PCD) including apoptosis, necrosis, pyroptosis and ferroptosis, while special emphasis is placed on the development of synthetic agents for the therapeutic modulation of post-radiation tumor cell fate decisions to facilitate tumor cell eradication, focusing on their therapeutic utility for amplifying the RT-induced direct tumor cell damage as well as promoting the post-IR antitumor immunity. We envision that these synthetic cell fate regulatory technologies could provide new avenues for improving radiotherapeutic efficacy.

Rationale: Gastric cancer (GC) is a leading cause of cancer-related mortality, particularly in advanced stages where prognosis and targeted treatment remain challenging. The glycocalyx, a dense network of glycans and glycoproteins, is critical for tumor progression and immune evasion, yet its molecular signatures are poorly understood. This study investigates glycan-based biomarkers of aggressiveness, focusing on paucimannosidic N-glycans, a previously underexplored glycosylation pattern in cancer.Methods: High-throughput N-glycome analysis was performed on gastric tumors of varying aggressiveness, followed by Galanthus Nivalis Lectin (GNL) immunostaining to assess paucimannosidic glycans across tumor stages. Comparative analysis was performed against clinically relevant GC biomarkers (E-cadherin, p53, MSI, sTn, sLeA). TCGA analysis correlated key paucimannose-associated glycosyltransferases with clinical outcomes. Glycoproteomics identified glycoproteins carrying paucimannoses, later validated using immunoassays in tumor tissues for clinical relevance. Additionally, serum samples were analyzed to evaluate the non-invasive potential of GNL reactivity and associated glycoproteins.Results: Aggressive gastric tumors were significantly enriched in paucimannosidic N-glycans, a feature not previously reported in this malignancy. Lectin immunoblotting confirmed their disease specificity, with expression increasing with tumor progression. GNL staining outperformed established biomarkers in prognostic accuracy. TCGA analysis of more than 400 cases showed a strong correlation between high paucimannose-associated glycosyltransferase expression and poor prognosis. Glycoproteomics unexpectedly revealed paucimannose N-glycans primarily on intracellular ribosomal proteins, though key membrane proteins like MMP9 displayed aberrant paucimannosylation. MMP9 expression increased with tumor stage and grade, with tumors co-expressing MMP9 and paucimannosidic glycans exhibiting the worst prognosis. In serum, only MMP9 demonstrated diagnostic potential as a circulating biomarker, whereas GNL did not show a significant association.Conclusions: This study provides the first comprehensive characterization of the GC glycome, linking paucimannosidic N-glycans to tumor aggressiveness and poor clinical outcome. These glycans demonstrated superior prognostic performance compared to established clinical biomarkers. Their association with MMP9 further suggests a key role in disease progression. Together, these findings suggest that alterations in N-glycosylation, including paucimannosylated glycoproteins, hold promise for future prognostic and therapeutic applications in gastric cancer.

Background: Acute liver injury (ALI), a highly perilous clinical condition triggered by diverse etiological factors, frequently progresses to acute liver failure with life-threatening consequences. However, due to the limited intervention time window for ALF, donor shortages, challenges in utilizing marginal grafts, surgical complexity and risks, and the high economic burden, developing novel therapeutic strategies targeting ALI-induced ALF has become imperative.Methods: Through transcriptome analysis, we determined that ferroptosis is a key driver in the pathogenesis of ALI. To combat hepatocyte ferroptosis, we designed a novel mitochondria-targeted nanotuner (CPTD) for regulating mitochondrial oxidative stress and iron homeostasis imbalance during ALI. This nanotuner features a cerium oxide (CeO₂) nanozyme core with a polydopamine (PDA) coating, functionalized with triphenylphosphonium (TPP) for mitochondrial targeting and deferoxamine (DFO) for iron chelation. In vitro and in vivo experiments evaluated CPTD's ability to target mitochondria and the labile iron pool (LIP).Results: The nanotuner demonstrates dual regulatory capacity by effectively accumulating in hepatic mitochondria to concurrently scavenge reactive oxygen species (ROS) and sequester labile iron ions, thereby rectifying mitochondrial oxidative stress and iron dyshomeostasis. Comprehensive evaluations across multiple ALI models, mainly including hepatic ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity, revealed that CPTD robustly inhibits ferroptosis, mitigates oxidative damage, attenuates inflammatory responses, and preserves hepatic function.Conclusions: Our findings establish this dual-targeting nanotuner as a promising therapeutic strategy for ALI, providing novel insights into mitochondrial redox and iron homeostasis modulation.