Myocardial ischemia/reperfusion injury (MI/RI) is driven by a cascade of pathological events, including oxidative stress and the activation of novel cell death pathways such as ferroptosis. The stage-specific shift in dominant cell death modalities coupled with the inherently low bioavailability of conventional therapeutics in the rhythmically contracting heart critically constrain the efficacy of single-target interventions. Here, we developed a spatiotemporally controllable “therapeutic relay” strategy based on a metal–phenolic network-hybridized liposomal system (MP@T NPs). During the early reperfusion phase, the tannic acid–cerium (TA–Ce) network shell exhibits reactive oxygen species (ROS) scavenging and anti-inflammatory activities, thereby effectively mitigating apoptosis and autophagy-associated cell death. Concurrently, its high affinity for collagen ensures the prolonged and targeted retention of the nanoparticles at the injury site. Upon the initiation of ferroptosis, ultrasound (US) irradiation subsequently induces the phase transition and vaporization of perfluoropentane (PFP), triggering the on-demand release of the arachidonate lipoxygenase (ALOX) inhibitor ML351 to precisely suppress ferroptotic cell death. This sequential action inhibits ferroptosis by downregulating ACSL4 and upregulating GPX4, thereby attenuating lipid peroxidation and restoring mitochondrial function in H9c2 cells. In the MI/RI rat model, MP@T NPs reduced ROS levels and iron deposition, suppressed inflammation, and restored the ejection fraction and fractional shortening. This novel, noninvasively regulated therapeutic platform enables temporally precise intervention in the key pathological cascades of MI/RI, offering a promising multitarget approach for enhancing myocardial salvage and functional recovery.

Apoptosis resistance, the severely immunosuppressive tumor microenvironment (TME), and the self-adaptive survival mechanisms of tumor cells significantly impair the efficacy of tumor therapies, driving us to seek more effective antitumor therapeutics that can induce devastative tumor death modalities. Herein, we present a biomineralized bacterial outer membrane vesicles-based nanocomposite (Gd-ZIF@OMV@DC661) designed to activate pyroptotic dualism while simultaneously blocking the pyroptotic checkpoint. Upon internalization by tumor cells, the nanocomposite undergoes acid-responsive degradation, releasing Zn2+, Gd3+, DC661 (a potent autophagy and lysosomal function inhibitor), and exposing OMVs with pyroptotic performance. Cellular oxidative stress induced by Zn2+ and Gd3+, in conjunction with lipopolysaccharide (LPS) presented by the outer membrane vesicles (OMVs), activates both caspase-1-dependent canonical and caspase-11-dependent non-canonical pyroptotic pathways. To counteract the tumor’s adaptive autophagic mechanisms—known as a pyroptotic checkpoint to suppress pyroptosis, the released DC661 inhibited tumor autophagy, deactivated pyroptotic actuators, amplified tumor pyroptosis, and simultaneously induced lysosomal cell death by causing lysosomal lipid peroxidation, thereby inducing robust immunogenic cell death. The consequent release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) facilitates dendritic cell (DC) maturation and T-cell activation, driving a potent adaptive immune response. Furthermore, the presence of Gd³⁺ allows for real-time tumor tracking via T1-weighted magnetic resonance imaging. Overall, this study presents a multifunctional, theranostic nanoplatform that integrates dual pyroptosis, lysosomal cell death, and immune activation, offering a promising strategy for immune-silent solid tumor treatment.

Abstract Background Pathological intraplaque neovascularization, vascular leakage, and fibrous cap thinning contribute to vulnerable atherosclerotic plaque rupture. Platelet- derived growth factor-BB (PDGF-BB) has been shown to promote pericyte recruitment, thereby stabilizing the microvascular structure, and to induce phenotypic modulation of vascular smooth muscle cells (VSMCs), which enhances fibrous cap thickness and reinforces plaque stability. Nevertheless, systemic protein delivery is limited by rapid clearance and potential off-target effects. Methods We developed PDGF-BB mRNA-loaded lipid nanoparticle–poly(lactic-co- glycolic acid) nanobubble complexes (LNPmRNA@PLGA) and used low-intensity focused ultrasound (LIFU) to enhance plaque-targeted delivery. Cellular uptake, PDGF- BB expression, vascular mural-cell responses, plaque histology, hemodynamics, and proteomic changes were evaluated in vitro and in ApoE −/− Fbn1 C1041G+/− mice. Results LIFU enhanced nanocomplex uptake and PDGF-BB expression, promoted vascular smooth muscle cell proliferation, migration, and phenotypic switching, and increased pericyte coverage. In vivo, LIFU plus LNPmRNA@PLGA reduced the plaque vulnerability index by 78.2% and the neovascularization area by 67.3% compared with controls, while increasing collagen deposition and improving carotid hemodynamics. Conclusions LIFU-responsive delivery of PDGF-BB mRNA stabilized vulnerable plaques by promoting neovessel maturation and strengthening the fibrous cap. This strategy provides a spatially controlled framework for therapeutic remodeling of high-risk atherosclerotic plaques. Research Perspective What New Question Does This Study Raise? Can spatially controlled PDGF-BB mRNA delivery simultaneously mature intraplaque neovessels and reinforce the fibrous cap without the systemic effects associated with recombinant PDGF-BB? What Question Should Be Addressed Next? Future studies should define the therapeutic window, durability, and long-term safety of LIFU-triggered PDGF-BB mRNA delivery in large-animal models that more closely reproduce human plaque rupture.

Zinc ions (Zn2+) overload is considered an exceptionally safe and ideal approach for pyroptosis-mediated tumor treatment. However, achieving efficient and safe induction of tumor-specific Zn2+ overload remains a significant challenge. This study pioneers the concept of “sono-activated Zn2+ storm”, developing a sono-activated and tumor microenvironment (TME)-responsive nanoplatform, Zn-TCPP@CaCO3, which enables a precise and spatiotemporally controllable induction of Zn2+ overload at the tumor site. Specifically, Zn-TCPP@CaCO3 selectively releases meso-tetra-(4-carboxyphenyl) porphine (TCPP) and delivers the “exogenous Zn2+” within the acidic TME. Upon tumor-site localized ultrasound irradiation, the sonosensitizer TCPP generates abundant reactive oxygen species (ROS) in situ, which oxidatively attack Zn-metallothionein complexes and effectively unlock the “endogenous Zn2+” reservoir. The synergistic influx of exogenous and endogenous Zn2+ drastically disrupts intracellular zinc homeostasis, further exacerbating oxidative stress by impairing mitochondrial function. This disruption initiates a self-amplifying positive feedback loop, ultimately inducing a potent “Zn2+ storm” that finally triggers tumor cell pyroptosis. The results demonstrate that this strategy not only effectively induces powerful antitumor effects, but also elicits a strong immunogenic response and significantly enhances the therapeutic efficacy of immune checkpoint inhibitors. Overall, this work provides valuable insights into the development of novel tumor specific ion interference therapies.

This study develops a novel multifunctional nanoplatform, modified polyethylene glycol-bismuth trioxide (mPEG-Bi2O3), synthesized via vacuum ball milling followed by ultrasonic liquid-phase exfoliation and surface PEGylation, to enhance the synergistic effects of sonodynamic therapy (SDT) and radiotherapy (RT). Characterization revealed that mPEG-Bi2O3 exhibits a thin-layered nanosheet structure (hydrodynamic size: 239.28 ± 4.32 nm; lattice spacing: 0.29 nm) and a zeta potential of -33.64 ± 0.80 mV. Notably, the nanoplatform demonstrated exceptional colloidal stability in physiologically relevant media, maintaining consistent size and surface charge over 7 d in serum-containing medium, which confirms the effectiveness of the PEG coating for biomedical applications. XPS analysis confirmed a mixed Bi3+/Bi5+ oxidation state, and deconvolution of the O 1s spectrum quantified the oxygen vacancy content at 11.02%, confirming a defect-rich structure. Successful PEG grafting was verified by Fourier transform infrared spectroscopy and quantified by thermogravimetric analysis, showing a grafting content of ~13.59 wt %. Under low-intensity focused ultrasound (LIFU), mPEG-Bi2O3 significantly enhanced reactive oxygen species generation, leading to a marked reduction in intracellular glutathione levels. In vitro cytotoxicity studies demonstrated favorable selectivity, with lower toxicity toward normal endothelial cells compared to 4T1 cancer cells, and the combination of mPEG-Bi2O3 and LIFU induced apoptosis in 4T1 cells. In vivo studies showed that intravenous administration of mPEG-Bi2O3 in tumor-bearing mice resulted in peak tumor accumulation at 24 h (0.17 ± 0.03 %ID/g), correlating with a significant 87.82% ± 4.77% reduction in tumor volume after 14 d of treatment when combined with LIFU and RT (10 Gy), superior to dual-modality treatments. Immune profiling indicated enhanced dendritic cell maturation, increased tumor-infiltrating CD8+ T cells, and reduced regulatory T cells, demonstrating immune microenvironment remodeling. Collectively, mPEG-Bi2O3 presents a surface-engineered strategy for potent SDT-RT synergy with demonstrated biosafety, showing promising potential for solid tumor treatment.

Abstract Purpose To develop a radiomics model utilizing contrast-enhanced computed tomography (CECT) for predicting the prognosis of post-acute pancreatitis diabetes mellitus (PPDM-A) and to explain the model’s internal predictive mechanisms using Shapley Additive exPlanations (SHAP). Methods 226 PPDM-A patients were retrospectively recruited from three centers, with 107 in training, 46 in internal, and 73 in external cohorts. There were 34, 15 and 28 patients with complications in each cohort. The complications included microvascular complications, infection, diabetic ketosis and hypoglycemia. In PPDM-A patients’ first pancreatitis episode, 2398 radiomics features were extracted from CECT images (arterial and venous phases). FeAture Explorer generated the machine learning pipeline and selected important radiomics features. Gaussian processes classifiers built radiomics and clinical-radiomics models, while Naive Bayes classifiers built the clinical model. The SHAP method was applied to provide insights into the model’s predictive process. Results The radiomics model predicted PPDM-A complications with the area under the receiver operating characteristic curve (AUC) of 0.95, 0.888, and 0.948 in training, internal, and external cohorts. In external cohort, the radiomics model significantly outperformed the clinical model (AUC 0.948 vs. 0.713, p = 0.002), while the combined model showed no significant difference from the radiomics model (AUC 0.933 vs. 0.948, p = 0.638). The SHAP technology provided physicians with insights into the global and individual impacts of radiomic features on model predictions. Conclusion The CECT‑based radiomics model showed favorable prognostic performance for the prognosis of PPDM‑A. SHAP analysis interpreted the model’s mechanism, enhancing its clinical reliability and transparency.

Correction for 'MnO2-based nanoparticles remodeling tumor micro-environment to augment sonodynamic immunotherapy against breast cancer' by Haiqin Liao et al., Biomater. Sci., 2025, 13, 2767-2782, https://doi.org/10.1039/D5BM00189G.

Background Sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, its therapeutic efficacy is significantly limited by the hypoxic tumor microenvironment, particularly in breast cancer. To address this limitation, we developed a biomimetic nanoplatform capable of generating oxygen within the tumor microenvironment to enhance SDT performance. Methods Poly (lactic-co-glycolic acid) (PLGA) nanoparticles were co-loaded with catalase and the sonosensitizer IR780 and subsequently coated with 4T1 cancer cell membranes (CIP@4T1m NPs). A series of in vitro and in vivo experiments were conducted to evaluate tumor-targeting capability, hypoxia alleviation, singlet oxygen ( 1 O 2 ) generation, antitumor efficacy, induction of immunogenic cell death (ICD), and activation of antitumor immune responses. Results The resulting CIP@4T1m NPs were successfully fabricated and exhibited preferential accumulation in 4T1 tumor cells and orthotopic 4T1 tumor-bearing mice. Both in vitro and in vivo studies demonstrated that the nanoplatform partially relieved tumor hypoxia and significantly enhanced SDT-mediated 1 O 2 production and antitumor effects. Moreover, CIP@4T1m NPs combined with ultrasound induced ICD-associated changes, promoted dendritic cell maturation, facilitated the polarization of tumor-associated macrophages from the M2 to M1 phenotype, reduced regulatory T cell populations, and increased intratumoral CD8 + T-cell infiltration. Conclusion This work describes a biomimetic nanoplatform that integrates homologous targeting with enzymatic oxygen generation to enhance SDT efficacy and promote antitumor immune responses in an orthotopic 4T1 breast cancer model. The proposed strategy offers a potential approach to mitigate hypoxia-associated limitations in cancer therapy.

The maintenance of intracellular calcium ion (Ca2 +) homeostasis plays a pivotal role in regulating both cellular survival and immunoregulatory pathways. However, achieving safe and precise manipulation of these messenger ions to engineer next-generation antitumor immunotherapies remains a formidable challenge. Here, we reveal an organelle crosstalk paradigm that harnesses innate Ca2+ dynamics to drive calcipoptosis-mediated antitumor immunity, bypassing the limitations of conventional exogenous calcium-dependent strategies. A modular peptide-programmed nanoagonist was designed to activate self-supplied calcium influx between Ca2+-rich and Ca2+-sensitive organelles by inducing endoplasmic reticulum stress and opening mitochondrial calcium transport channels under ultrasound irradiation. Moreover, the targeted dysfunction of dual-organelles leads to the activation of the caspase-dependent apoptotic pathway and the release of a cascade of damage-associated molecular patterns to promote dendritic cell maturation and cytotoxic T-cell infiltration. Additionally, Ca2+ dysregulation polarizes macrophages into a pro-inflammatory phenotype and stiffens cancer cells to establish biochemical and mechanical immunosurveillance. The nanoagonist demonstrated potent ablation of primary tumors and suppression of metastatic growth in breast and liver cancer models. Overall, this work enables customizable subcellular bioenergetic disruption without systemic toxicity risks, which pioneers a translatable strategy that redefines the frontier of calcium-based immunotherapy.

Previous studies have established associations between indoor air pollution and loss of muscle mass. While indoor ventilation improves indoor air quality, its association with low muscle mass (LMM) remains unexplored. We investigated the association between indoor ventilation frequency (IVF) and LMM in older Chinese adults. Utilizing data from the China Longitudinal Healthy Longevity Survey (CLHLS), IVF was assessed via self-reported weekly window-opening frequency in each season of the past year. LMM was defined using appendicular skeletal muscle mass (ASM) prediction equations. Binary logistic regression models were employed to evaluate the association between IVF and LMM, with subgroup and sensitivity analyses conducted. After adjusting for covariates, participants with intermediate IVF (OR: 0.805; 95% CI: 0.669–0.969) and high IVF (OR: 0.818; 95% CI: 0.684–0.979) were 19.5% and 18.2% less likely to develop LMM, compared with participants with low IVF. The probability of LMM in the spring was 25.3% (OR: 0.747; 95% CI: 0.581–0.961) and 23.3% (OR: 0.767; 95% CI: 0.597–0.985) lower in the middle and high IVF elderly populations, respectively, whereas the probability of LMM in the spring was 36.5% (OR: 0.625; 95% CI: 0.474–0.824) and 34.1% (OR: 0.659; 95% CI: 0.501–0.868). The association between IVF and LMM was statistically significant (p < 0.05) in gender, age, residence, living arrangement, marital status, economic situation, work, smoking, drinking, exercise, cooking ventilation, life satisfaction, self-rated health, hypertension, diabetes, heart disease, dementia, and NO2. Interaction analyses showed a significant interaction effect between the drinking subgroup and IVF (P for interaction < 0.05). Higher IVF is significantly associated with a lower risk of LMM. Optimizing ventilation practices may mitigate LMM burden in older adults, informing personalized health strategies.

Despite the encouraging developments in tumor immunotherapy, the complex tumor microenvironment (TME) and abnormal energy metabolism persist as key factors facilitating immune escape. Recent research has emphasized the significant potential of the Manganese ions (Mn2+) as a “immune ion reactors” have the potential to stimulate cGAS-STING signaling pathway in modulating tumor immunotherapy. However, their efficacy is limited by insufficient targeting and lack of tumor specificity. To address these challenges, we have developed a nano-drug named as LT@MnO@MON-HA (LMMH), which incorporates manganese oxide (MnO) nanoparticles as the core and organic mesoporous silica as the outer layer. The mitochondrial glycolysis inhibitor lonidamine (LT) is encapsulated within the mesopores of LMMH and subsequently coated with hyaluronic acid to achieve precise tumor-targeted drug delivery. After reaching the tumor site, LMMH can decompose in the reducing and acidic TME, releasing LT and Mn2+. Once internalized by cells, LT rapidly localizes to mitochondria via functional groups, disrupting mitochondrial metabolism and increasing intracellular reactive oxygen species levels. Mn2+ catalyze the conversion of hydrogen peroxide (H₂O₂) into more cytotoxic hydroxyl radicals (·OH), thereby enhancing chemodynamic therapy (CDT). The mesoporous silica shell of LMMH is capable of depleting glutathione in the TME, enhancing CDT. Moreover, LMMH functions as an agonist of the cGAS-STING pathway, stimulating cytokine release and activating effector T cells, which in turn triggering systemic immune responses against primary and metastatic cancers. Collectively, these finding highlights the dual mechanisms by which LMMH enhances combination immunotherapy by regulating the TME and tumor metabolism.

Atherosclerosis and vessel wall trauma induce vascular smooth muscle cell (VSMC) phenotypic modulation, leading to plaque cap growth and postintervention restenosis. Our systems biology approach identified RNA binding protein, mRNA processing factor (RBPMS) as a conserved, VSMC- specific gene associated with VSMC modulation in atherosclerosis. RBPMS gene expression positively correlates with VSMC contractile markers in human and murine atherosclerotic arteries as well as in two vascular injury models during the postinjury intimal hyperplasia phase. RBPMS promotes contractile VSMC differentiation, reduces plaque cap development in high- fat diet- fed apolipoprotein E- null (ApoE-/-) murine atherosclerotic arteries, and inhibits intimal hyperplasia. Mechanistically, the RBPMS protein interacts with the myocardin (MYOCD) pre-mRNA and enhances MYOCD_v3/MYOCD_v1 transcript balance through alternative exon 2a splicing. RBPMS promotes the VSMC contractile phenotype and reduces their fibroproliferative activity in a MYOCD_v3a- dependent manner. RBPMS enhances Myocd_ v3/Myocd_v1 transcript balance in both atherosclerotic and injured vessels. RBPMS may inhibit VSMC- driven plaque cap development and intervention- induced restenosis.

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive behavior, immunosuppressive tumor microenvironment, and lack of effective targeted therapies. To address these limitations, we developed a magneto-photo-acoustic responsive nanoplatform (MnFe2O4-erastin-perfluoropentane nanoparticles [MEPNPs]). This nanoplatform features 3-tiered therapeutic innovations: (a) Multimodal imaging-guided precision therapy: The superparamagnetic property of MnFe2O4 enabled magnetic resonance and photoacoustic imaging, allowing real-time visualization of tumor margins. (b) Spatiotemporally controlled ferroptosis activation: Magnetic targeting enhanced the tumor accumulation of MEPNPs, while near-infrared irradiation triggered perfluoropentane vaporization for burst erastin release. This dual strategy combinationally suppressed glutathione peroxidase 4 and amplified the accumulation of lipid peroxides, achieving the amplification of ferroptosis. (c) Immunogenic tumor microenvironment reprogramming: MEPNP-induced immunogenic cell death promoted dendritic cell maturation and CD8+ T-cell infiltration, effectively converting immunologically "cold" TNBC tumors into "hot" phenotypes. In TNBC models, MEPNP treatment elicited remarkable therapeutic outcomes: primary tumor suppression, reduction in lung metastasis, and an extended median survival period exceeding 45 d. The transcriptome sequencing results showed that there were 6,198 differentially expressed genes in the treatment group. These included the up-regulation of ferroptosis drivers such as SLC39A14, as well as the down-regulation of antioxidant regulators such as SLC7A11 and SLC3A2. Additionally, Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed that the "ferroptosis" and "T-cell differentiation" pathways were specifically activated. This work establishes a novel "theranostic-immunomodulatory" paradigm that integrates magnetic targeting, ferroptosis potentiation, and immunogenic-cell-death-mediated immune memory. By orchestrating physical energy conversion, MEPNPs provide a spatially focused and immunologically amplified strategy to overcome TNBC therapeutic resistance.

Background: Most anticancer agents induce tumor apoptosis, but they often lack immunogenicity and display limited success when combined with mainstream immunotherapies, thus killing cancer cells through multiple cell death modalities as well as switching immune-off tumors to immune-on is a strategy with great promise. To this end, we developed a CPApoptosis (cuproptosis, pyroptosis, apoptosis) nano-actuator for immunologically cold solid tumors. Methods: In this study, elesclomol (ES), a mitochondrial targeting copper transporter, was encapsulated within bacterial outer membrane vesicles (OMVs). These OMVs were then surface-modified via metal-phenolic self-assembly using Cu2+ and tannic acid (TA). Results: The Cu2+ and ES were released from the OMVs in a pH-dependent manner. OMV activated the non-canonical pyroptotic pathway, leading to cell membrane rupture. Cu2+ on the one hand was transported to the mitochondria for cuproptosis facilitated by ES, on the other hand, Cu2+ was reduced into Cu+ by TA, which catalyzed ROS production to induce oxidative apoptosis. Simultaneously, TA degraded glutathione (GSH), sensitizing cells to cuproptosis. The multifactorial cell death mechanisms led to the release of immunogenic factors from lysed tumor cells, stimulating dendritic cell maturation and recruiting cytotoxic T cells. This immune response was further amplified by αPD-L1 antibody treatment. Conclusion: The CPApoptosis nano-actuator represents a promising approach to enhance current cancer therapies, inducing both tumor cell death and a robust immune response, with the potential for long-lasting protective effects.

Sorafenib (Sor), a first-line drug for advanced hepatocellular carcinoma (HCC), can potently induce tumor ferroptosis by inhibiting the cystine/glutamate countertransporter (System Xc-). However, tumors can upregulate the expression of ferritin to prevent its progression to ferroptosis, which induces Sor insensitivity. In this study, ultrasound (US) reaction nanoparticles (NPs) composed of ferritin-homing peptide (HKN15)-modified poly (lactic-coglycolic acid) and the acoustic droplet vaporization (ADV)-responsive material perfluorhexane (PFH) were fabricated. Owing to the positive feedback effects of HKN15 and ferritin overexpression, the NPs (HKN15@PLGA-PFH) specifically accumulate around ferritin in HCC cells. With US irradiation at pathological regions, the spatiotemporally ADV effect can influence the stability of the iron pool named ferritin, which releases cellular iron, leading to inevitable ferroptosis through the production of ROS and lipid peroxidation and a reduction in GSH and GPx4. Overall, the cytotoxic effect of the combined treatment group was 1.6 times greater than that of the Sor-only group against HCC cells, which highlights an innovative potential strategy for increasing the therapeutic efficacy of Sor through combined treatment to sensitize HCC cells to ferroptosis.

The computational burden of the iterative sampling process remains a major challenge in diffusion-based LowLight Image Enhancement (LLIE). Current acceleration methods, whether training-based or training-free, often lead to significant performance degradation, highlighting the trade-off between performance and efficiency. In this paper, we identify two primary factors contributing to performance degradation: fitting errors and the inference gap. Our key insight is that fitting errors can be mitigated by linearly extrapolating the incorrect score functions, while the inference gap can be reduced by shifting the Gaussian flow to a reflectance-aware residual space. Based on the above insights, we design Reflectance-Aware Trajectory Refinement (RATR) module, a simple yet effective module to refine the teacher trajectory using the reflectance component of images. Following this, we introduce Reflectance-aware Diffusion with Distilled Trajectory (ReDDiT), an efficient and flexible distillation framework tailored for LLIE. Our framework achieves comparable performance to previous diffusion-based methods with redundant steps in just 2 steps while establishing new state-of-the-art (SOTA) results with 8 or 4 steps. Comprehensive experimental evaluations on 10 benchmark datasets validate the effectiveness of our method, consistently outperforming existing SOTA methods. Code is available at project page.

The tumor microenvironment (TME) is characterized by a complex array of factors, including aerobic conditions, high glutathione (GSH) levels, acidic pH, and elevated hydrogen peroxide (H2O2) content, all of which promote cancer progression and contribute to poor prognosis. Fortunately, these challenges can be addressed using MnO2-based nanomaterials. In this study, we have designed and synthesized a Curcumin/MnO2@PLGA@4T1 cell membrane (CMP@4T1m) system aimed at remodelling the TME and enhancing sonodynamic immunotherapy for breast cancer. Through the homologous targeting ability of 4T1m, CMP@4T1m efficiently accumulates at the tumor site. Upon ultrasound irradiation, curcumin (Cur) acts as a sonosensitizer, generating cytotoxic reactive oxygen species (ROS) that induce immunogenic cell death (ICD), activate T-cell responses, and repolarize protumoral M2-like macrophages to antitumoral M1-like macrophages. In the TME, which is mildly acidic and enriched with GSH and H2O2, MnO2 not only oxidizes GSH to glutathione disulfide (GSSG) but also reacts with H2O2 and H+ to produce oxygen, alleviating hypoxia and significantly enhancing the sonodynamic immunotherapy effect. Additionally, Mn2+ generated during this process converts H2O2 into cytotoxic hydroxyl radicals (˙OH). This study thus lays the foundation for advancing cancer nanomedicine, offering a novel approach that integrates TME remodelling with sonodynamic immunotherapy.

Olfactory receptor 6A2 (OR6A2) signaling stimulates atherogenic NLRP3 inflammasome activation in vascular macrophages (Mϕs). Current evidence suggests that interleukin-1 receptor type 1 (IL-1R1)/Toll-like receptor (TLR) signaling may modulate this OR6A2-mediated inflammasome response. However, the role of and mechanism(s) by which IL-1R1/TLR signaling modulates the inflammasome response and resultant atherosclerosis remain unknown. We discovered that the interaction between β-arrestin-2 (βarr2) and OR6A2's intracellular loop 3 (OR6A2ICL3) mediates OR6A2 endocytosis, thereby inhibiting OR6A2-mediated Mϕ inflammasome activation. IL-1R1/TLR signaling promotes coupling of the coiled-coil domain of tumor necrosis factor receptor-associated factor 6 (TRAF6CCD) with βarr2, thereby blocking OR6A2ICL3-βarr2 binding, inhibiting βarr2/AP2-mediated OR6A2 internalization, and potentiating Mϕ inflammasome activation. Consistently, blocking TRAF6CCD-βarr2 coupling in vascular Mϕs inhibits octanal-induced atherosclerosis in high-cholesterol-diet-fed Ldlr-/- mice. Additionally, IL-1R1/TLR-activated βarr2K295 deSUMOylation drives TRAF6CCD-βarr2 coupling in Mϕs, and βarr2K295 deSUMOylation in vascular Mϕs promotes OR6A2-mediated atherosclerosis in high-cholesterol-diet-fed Ldlr-/- mice. In conclusion, IL-1R1/TLR-induced TRAF6CCD-βarr2 coupling, by inhibiting βarr2/AP2-mediated OR6A2 endocytosis, promotes atherogenic OR6A2-mediated NLRP3 inflammasome activation in vascular Mϕs.

20% acute pancreatitis (AP) develops into severe AP (SAP), a global health crisis, with an increased mortality rate to 30%-50%. Mitochondrial damage and immune disorders are direct factors, which exacerbate the occurrence and progression of AP. So far, mitochondrial and immunity injury in SAP remains largely elusive, with no established treatment options available. Immunomodulation is a promising approach to treat pancreatitis. Herein, we proved that Tuftsin (TN), a vital endogenous immunomodulator, can inhibit SAP, while it is limited by extremely short biological half-life, low bioavailability, and the inconvenience of administration. Nano platform is the positive choice. Interestingly, we found that the activated P2X7 signaling was closely associated with the enhanced pancreatic inflammation via damaging mitochondrial function in SAP. Herein, we engineered a nanoplatform containing a Se-Se bond responsive for ROS to deliver TN, namely, DSPE-Se-Se-MPEG@TN (DSSM@TN), contributing to increases in TN's half-life and bioavailability. We synthesized TN-loaded ROS-responsive DSPE-Se-Se- MPEG@TN liposomes (DSSM@TN NPs) via a one-step emulsification method, which exhibited good biosecurity, high stability, suitable size, favorable ROS responsiveness and biocompatibility, as well as excellent capability for releasing TN during oxidative stress and inflammation environment. Moreover, the Se-Se bond with ROS-responsive ability was first proved to play a vital role for TN-loaded liposomes to enhance its anti-inflammation and antioxidant abilities via targeting damaged mitochondria during SAP progression. Mechanistically, DSSM@TN targeting damaged pancreas simultaneously inhibits mitochondrial dysfunction and inflammation in vivo and vitro via mitochondrial P2X7 signaling-impaired Nrf2/HO-1 signaling-inhibited PINK1/PARKIN pathway. Consequently, such a ROS-responsive immunotherapy nanomedicine targeted mitochondria holds great potential in facilitating substantial clinical progress in SAP treatment.

It is recommended that ≥ 5 pathological N1a central lymph node metastases required a second total thyroidectomy after unilateral thyroidectomy In papillary thyroid carcinoma (PTC) patients. We aimed to develop a preoperative nomogram integrating conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) to accurately predict high-volume central lymph node metastasis (HVCLNM) in PTC. Patients with pathologically confirmed PTC were enrolled in our study between May 2021 and May 2024. Overall, a total of 867 patients were enrolled, and they were split into training and validation datasets at random in a 7:3 ratio. A nomogram predicting HVCLNM probability was developed in the training dataset using conventional US and CEUS characteristics. Model performance was assessed using the area under the curve (AUC), calibration, and decision curve analysis (DCA). A total of 607 patients (mean age, 42 ± 11.8 years, M/F = 142/465) and 260 patients (mean age, 42 ± 11.4 years, M/F = 54/206) were enrolled in the training and validation datasets, respectively. LASSO logistic regression selected five imaging features with non-zero coefficients: size, multifocality, enhancement direction, peak intensity, and US-reported LN status. The nomogram incorporating these factors demonstrated strong predictive performance for HVCLNM, with mean AUCs of 0.9149 (95