Resistance to immunotherapy remains a central challenge in advanced hepatocellular carcinoma (HCC). The role of systemic factors, particularly the metabolic fitness of the circulating immune reservoir, in driving this resistance remains poorly understood. This study aimed to identify pre-treatment metabolic signatures in peripheral blood mononuclear cells (PBMCs) that predict therapeutic response and to elucidate the underlying mechanisms of T-cell dysfunction. We performed integrated multi-omics analyses, including proteomics, metabolomics, lipidomics, and phosphoproteomics, on pre-treatment PBMCs from a cohort of HCC patients receiving anti-PD-1 immunotherapy-based combination treatment. Predictive metabolic signatures were identified, and key mechanisms were validated using flow cytometry, confocal microscopy, and molecular analyses. An enhanced lipid metabolic signature in pre-treatment PBMCs was identified as a powerful and independent predictor of poor immunotherapy response and survival. We found that a lipid-enriched plasma milieu in non-responders imposes a metabolic constraint on PBMCs. Specifically, CD36 upregulation correlates with increased lipid uptake and accumulation of glycerophospholipids and sphingolipids, triggering sub-lethal ferroptotic stress (characterized by ferroptosis molecular hallmarks and functional impairment in viable cells without overt cell death) and subsequent T cell exhaustion. This ferroptotic stress state exhibited lipid peroxidation, reduced GPX4 expression, and elevated intracellular iron (Fe2+), and was mechanistically sustained by suppressed AKT survival signaling coupled with hyperactive inflammatory pathways (MAPK, NF-kappa B). Importantly, this metabolic dysfunction was reversible upon blocking lipid peroxidation. The systemic metabolic fitness of circulating PBMCs is an important determinant of immunotherapy efficacy in HCC that complements tumor-intrinsic factors. Our findings provide a new framework for developing non-invasive predictive biomarkers and demonstrate that PBMC ferroptotic stress is mechanistically reversible, providing a rationale for evaluating systemic metabolic modulation as a strategy to enhance immunotherapy outcomes.

BACKGROUND:Untargeted LC-MS metabolomics converts chromatographic ion signals into feature tables used for downstream comparison, annotation, and biomarker discovery. However, widely used preprocessing workflows often return discordant feature lists and missingness patterns from the same raw data, limiting reproducible quantitative interpretation. Continuous wavelet transform (CWT)-based peak detection is central to several workflows, yet its scale-normalization convention was inherited from energy-preserving signal analysis rather than area-oriented chromatographic integration. The problem addressed here is whether CWT normalization itself creates scale-selection and integration-boundary bias in LC-MS feature-table construction. RESULTS:Under a Gaussian reference peak model with a Mexican-hat wavelet, amplitude-preserving 1/a normalization produced a defined optimum at a = √2σ and model-derived integration boundaries at ±3σ, supporting area-oriented peak integration. We implemented this correction in MetaboQuality with shape-driven grouping and anchor-guided recovery, then evaluated it using authentic standards, pooled-QC replicates, public QC data, component ablation, comparator sensitivity, decoy controls, non-Gaussian simulations, and chemical-reference validation. In the primary pooled-QC benchmark before post-detection filling, MetaboQuality produced 4029 complete groups with RSD <30%, compared with 2461 for XCMS and 1672 for MZmine 4. At the stricter RSD <10% threshold, MetaboQuality yielded 931 complete groups before filling versus 526 for the XCMS reference branch; after filling, MetaboQuality yielded 973 groups, compared with 678 for XCMS and 748 in the XCMS fitgauss sensitivity run. SIGNIFICANCE AND NOVELTY:The novelty lies in defining CWT normalization as an LC-MS-specific peak-integration determinant rather than a generic signal-processing detail. MetaboQuality links amplitude-preserving integration, shape-driven grouping, and anchor-guided recovery into a coordinated workflow, providing a principled route to more complete and reproducible feature tables without relying on unconstrained statistical imputation. This clarifies where algorithmic design can improve measurement consistency.

Mitochondrial metabolism is central to energy production and signaling, and its dysregulation drives cancer, neurodegenerative disorders, metabolic syndromes, and immune-inflammatory diseases. Targeted modulation of mitochondrial functions requires delivery systems capable of precise organelle localization and controlled therapeutic release. Among diverse nanoplatforms, lipid-based nanomaterials offer a unique combination of high biocompatibility, tunable membrane affinity, drug-loading flexibility and degradable, well-defined metabolic pathways, enabling efficient mitochondrial targeting while minimizing long-term toxicity. Lipid-based nanosystems, from conventional liposomes to lipid-polymer hybrids and emerging platforms, have rapidly advanced as versatile tools for mitochondrial intervention. This review outlines the structural attributes and therapeutic advantages of lipid-based nanosystems, assessing their applications in cancer, neurological, metabolic, and immune-inflammatory models. Beyond delivery, these systems actively regulate mitochondrial bioenergetics and signaling by reprogramming oxidative phosphorylation, and modulating reactive oxygen species dynamics. Key challenges include structural complexity, targeting specificity amid metabolic heterogeneity, long-term safety, and in vivo monitoring. By integrating advances across nanotechnology, bioenergetics, and disease biology, lipid-based nanosystems provide promising opportunities for precision mitochondrial medicine.

The development of colorectal cancer is closely related to the abnormal colonization of specific microorganisms in the tumor microenvironment. To address the challenges of exacerbated carcinogenesis and therapeutic resistance caused by Escherichia coli colonization in colorectal tumors, an innovative pH-and targeting-dual-responsive biomimetic nanodelivery system (CIP@EMV@CaCO3) based on bacterial membrane biomimetic strategies was developed. This system employs E. coli-derived membrane vesicles (EMVs) as carriers to achieve dual functions of homologous targeting for antibacterial purposes and immune activation, overcoming the low delivery efficiency bottleneck of traditional antibiotics. The innovative incorporation of calcium carbonate (CaCO3) enables both acidic environment-triggered lysosomal escape mediated by CO2 microbubbles and immunotoxicity regulation, achieving a bacterial clearance rate of 99.14%. Furthermore, the EMVs themselves were demonstrated to activate potent antitumor immune responses, inducing M1 macrophage polarization, promoting cytokine secretion, and enhancing T lymphocyte infiltration, resulting in a 98.02% tumor suppression rate in E. coli-infected colorectal cancer models. This study provides a multifunctional precision therapeutic paradigm for regulating microbe-tumor interactions, demonstrating significant translational value in the synergistic field of targeted antibacterial and immune therapy.

ABSTRACT Ultrasound (US)‐triggered reactive oxygen species (ROS) generation by nano‐sonocatalysts is vital for sonocatalytic therapy. However, the therapeutic effect is hindered by the low ROS generation yield owing to sluggish charge transfer and elusive active sites. Herein, in situ oxygen vacancies (Vo)‐engineered Pd‐TiO 2 sonocatalysts with spatially separated dual reactive sites are developed, which optimize charge kinetics and amplify ROS generation. Mechanism studies revealed that US‐induced Vo serves as an electron pump, activating the Pd–O–Ti transport channel, lowering interfacial barriers and steering electron migration from TiO 2 to Pd. This ordered charge redistribution tunes the d ‐band center of Pd, designating electron‐rich Pd sites as the primary active center for O 2 adsorption and activation to produce singlet oxygen ( 1 O 2 ). Concurrently, Vo‐mediated reconstruction of Ti 3d states strengthens orbital coupling with H 2 O at the Pd–O–Ti interface, dominating the activation of H 2 O to promote the generation of hydroxyl radical (•OH). This dual‐site configuration effectively lowers the activation energy barriers, which increases the rate constants of 1 O 2 and •OH generation by 5.0‐fold and 2.7‐fold, respectively, and ultimately achieving an 87.5% tumor inhibition efficiency. This work provides molecular insights into the charge transfer cascade and critical active centers in US‐activated Pd‐TiO 2 , offering a rational paradigm for designing high‐performance sonocatalysts.

Hypoxic non-small cell lung cancer (NSCLC) cells actively remodel lipid metabolism to construct a biochemical shield against lipotoxicity and oxidative stress. This adaptation drives a unidirectional phosphatidylcholine to triacylglycerol conversion with a Z-score of 4.253. While clinically equivalent doses of conventional X-rays (6 Gy) leave the hypoxia-adapted lipidome intact and yield zero significantly altered lipid species, carbon ions radiation markedly rewire the lipidome, significantly displacing 79 lipid species. Combining carbon ions radiation with HIF-1α knockdown amplifies this displacement to 134 altered lipids. This profound structural remodeling is dominated by the exhaustion of phosphatidylcholine and sphingomyelin. Crucially, this metabolic shift occurs without additional acute clonogenic cell kill compared to carbon ions alone. This effectively decouples metabolic disruption from immediate reproductive death. Untargeted metabolomics confirms the concurrent collapse of mitochondrial electron transport and glutathione buffering. Carbon ions radiation effectively abrogate the hypoxic lipid shield. The resulting metabolically compromised survivor subpopulation, stripped of its antioxidant defenses, reveals a pronounced vulnerability to lipid peroxidation. Conventional survival-based relative biological effectiveness systematically underestimates this effect. This study provides defined redox-targeted mechanisms for deploying ferroptosis inducers as precision combination therapies in hypoxic solid tumors.

Sonocatalytic therapy (SCT) is a non-invasive tumor treatment modality that utilizes ultrasound (US)- activated sonocatalysts to generate reactive oxygen species (ROS), whose production critically dependent on the electronic structural properties of the catalytic sites. However, the spin state, which is a pivotal descriptor of electronic properties, remains underappreciated in SCT. Herein, a Ti-doped zirconium-based MOF (Ti-UiO-66, denoted as UTN) with ligand-deficient defects is constructed for SCT, revealing the important role of the electronic spin state in modulating intrinsic catalytic activity. The defect-driven sonocatalytic mechanism is elucidated as follows: 1) structural defects alleviate the limitations of ligand-metal charge transfer, achieving a 2.1-fold enhancement in charge transfer efficiency; 2) spin polarization at Ti active sites reconfigures the d-orbital electron distribution, thereby increasing the density of spin-polarized electronic states near the Fermi level. Furthermore, Ti 3d-O 2p orbital hybridization lowers the adsorption energies of H2O and O2 by 2.5-fold and 1.6-fold, respectively, thereby facilitating interfacial redox reactions and leading to enhanced ROS generation. Notably, UTN combined with US achieves 86.07% tumor inhibition efficiency. This work establishes novel insights into defect engineering, spin-state modulation, and surface interfacial adsorption in SCT, providing a theoretical paradigm framework for designing of high-performance sonocatalysts.

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive macrophage infiltration and extracellular matrix deposition. The progress of IPF is promoted by M2 macrophages which produce pro-fibrotic factors and induce fibroblast differentiation. SESN3 was upregulated in lung tissues of IPF patients and mice with bleomycin-induced pulmonary fibrosis. However, the role of SESN3 in IPF and its related mechanisms remain largely unknown. METHODS:Here, we used IL-4/13 to induce macrophage M2 polarization in RAW264.7 cells and constructed a mouse model of pulmonary fibrosis by intratracheal injection of bleomycin. Adenoviruses targeting SESN3 were constructed to infect RAW264.7 cells and BLM-induced mice to assess the function of SESN3 in macrophage M2 polarization in the progress of IPF and mRNA-seq and Co-IP-MS analysis were performed to find the downstream factors. RESULTS:For in vitro experiments, SESN3 knockdown promoted the M2 polarization level, the release of pro-fibrosis factors and the activation of fibroblast, overexpression of SESN3 had an opposite trend. For in vivo experiments, the increased degree of pulmonary fibrosis in BLM mice was relieved after overexpression of SESN3. Meanwhile, overexpression of SESN3 repressed the increased macrophage M2 polarization level induced by BLM. Mechanically, FOSL2 was screened out through mRNA-seq and Co-IP-MS analysis due to its binding affinity with SESN3 and the observed downregulation of its downstream pro-fibrotic factor expression. The expression of FOSL2 in the nucleus was down-regulated after SESN3 overexpression. Under IL-4/13 treatment, the increased levels of macrophage M2 polarization and pro-fibrotic factors induced by SESN3 knockdown was recovered after knocking down FOSL2 in RAW264.7 cells. CONCLUSION:In summary, our study suggested that SESN3 regulated the IPF process through inhibiting macrophage M2 polarization by targeting the activity of FOSL2.

Inflammatory bowel disease (IBD) is characterized by excessive generation of reactive oxygen species and reactive nitrogen species (RONS) within the pro-inflammatory microenvironment. Conventional treatments often have serious side effects, making IBD management challenging. Here, a new cerium cluster, Ce12, with a formula of [Ce12(μ 3-O)8(μ 3-OH)8(μ 2-OH)6(ADA)18]∙3H2O∙3CH3CN (ADA- = 1-adamantanecarboxylate) was prepared and capped with β-cyclodextrin (β-CD) through self-assembly process involving the adamantane moiety of Ce12 and β-CD, resulting in Ce12@CD nanoparticles (NPs). Ce12@CD NPs, with good stability and biocompatibility, exhibit excellent reactive RONS scavenging activities due to the presence of a fraction of Ce3+ ions, offering potential for treating inflammatory diseases. Treatment significantly alleviated body weight loss, colon length reduction, and pathological injury of colon in mice with dextran sodium sulfate (DSS)-elicited colitis, thereby repairing the intestinal mucosal barrier and reducing inflammation. RNA sequence analysis revealed that the therapeutic effects of Ce12@CD NPs are highly correlated with IL-17 and TNF signaling pathways, thereby reducing inflammatory factors such as IL-1β and TNF-α, and alleviating intestinal inflammation. Additionally, Ce12@CD NPs successfully modulated DSS-induced gut microbiota imbalances. This work highlights the unique catalytic activity of Ce12@CD NPs in removing RONS and mimicking biological enzymes, showcasing their potential therapeutic applications for inflammatory disorders.

Pathogenic bacteria pose significant threats to human health. In recent years, escalating bacterial resistance against antibiotics has diminished their efficacy in treating infections like pneumonia, tuberculosis, and sepsis, making some cases virtually untreatable. Hence, there is an urgent demand for novel approaches to combat bacterial threats. Group IB metal-based nanomaterials including copper, silver, and gold have attracted considerable attention in the field of antibacterial research owing to their remarkable broad-spectrum bactericidal properties. Their high efficacy, ease of synthesis, and amenability for functionalization render group IB metal-based nanomaterials highly promising for diverse applications in the antibacterial domain. This review comprehensively elucidates on the bactericidal mechanisms and applications of IB-group metal-based nanomaterials in addressing bacterial infections. Additionally, insights into challenges associated with utilizing group IB metal-based nanomaterials for such purposes while outlining future directions of research are provided.

Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.

BACKGROUND:Substantial metabolic reprogramming accompanies the transition from cirrhosis to hepatocellular carcinoma (HCC), yet the metabolomic profile of cirrhotic liver tissue containing HCC remains insufficiently defined. METHODS:Metabolomic data from 203 cirrhotic tissue samples and 37 HCC tissue samples were obtained from the MetaboLights repository (dataset MTBLS8764). Multivariate statistical approaches, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA), were applied to delineate metabolic differences between groups. Discriminatory metabolites were identified using variable importance in projection (VIP) scores and fold-change analysis. Diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis for both individual metabolites and multi-metabolite panels. Complementary transcriptomic data were subjected to KEGG pathway enrichment and an integrated multi-omics evaluation to uncover biological pathways underlying disease progression. RESULTS:Multivariate analyses revealed significant metabolic divergence between cirrhotic and HCC tissues. PCA and supervised PLS-DA showed distinct group separation, and the OPLS-DA model demonstrated strong reliability (R²Y = 0.694, Q² = 0.39; p < 0.001). Fifty-seven metabolites showed significant differential abundance. ROC analysis indicated that combining four metabolites, 6-bromotryptophan, threonate, palmitoylcholine, and oleoylcholine, significantly improved diagnostic accuracy (AUC = 0.83, p < 0.001). KEGG enrichment analysis of metabolomic and transcriptomic datasets identified disrupted pathways in amino acid metabolism, oxidative stress, and lipid remodeling. Integrated multi-omics analysis further revealed coordinated alterations in the "choline metabolism in cancer" pathway, implicating this axis as a key contributor to HCC development. CONCLUSIONS:This comprehensive metabolomic framework identifies promising biomarkers and distinct metabolic signatures that differentiate cirrhosis from HCC and offers mechanistic insights to guide future diagnostic and therapeutic strategies.

The bacterial electron transport chain (ETC) plays a crucial role in biofilm energy metabolism and redox balance, making it a potential target for anti-biofilm treatment. Herein, mesoporous nanocarbon spheres loaded with Pt nanoparticles (CS-Pt) are developed to disrupt the bacterial ETC for photo-enhanced anti-biofilm. Under near-infrared laser irradiation, CS-Pt-treated biofilms show a positive shift of 0.6 eV in Pt 4f binding energy and a 1.76-fold increase in anodic current density, demonstrating that the electron loss from CS-Pt results in an enhanced electron transfer from CS-Pt to biofilm. Adding the electron quencher NH4Cl to the CS-Pt-containing biofilm sample results in reduced biofilm clearance, highlighting the critical role of enhanced electron transfer in effective biofilm eradication. Due to the multifunction of CS-Pt in inducing hyperthermia, reactive oxgen species generation, and interrupting bacterial ETC, the critical component of ETC, extracellular DNA, in methicillin-resistant Staphylococcus aureus (MRSA) biofilm is reduced by 89.8%, ultimately leading to a biofilm clearance of 90.3%. Additionally, CS-Pt achieve 99.5% biofilm eradication and expedites wound healing with a rate of 78.1% in a MRSA-infected wound model. We present an attractive approach for disintegrating biofilm through the synergistic effect of disrupting ETC, enzyme-like activity, and phototherapy, offering an innovative perspective on combating biofilm-associated infections.

OBJECTIVES:To investigate the effect of curcumin on lipid metabolism in non-small cell lung cancer (NSCLC) and its molecular mechanism. METHODS:The inhibitory effect of curcumin (0-70 μmol/L) on proliferation of A549 and H1299 cells was assessed using MTT assay, and 20 and 40 μmol/L curcumin was used in the subsequent experiments. The effect of curcumin on lipid metabolism was evaluated using cellular uptake assay, wound healing assay, triglyceride (TG)/free fatty acid (NEFA) measurements, and Oil Red O staining. Western blotting was performed to detect the expressions of PGC-1α, PPAR-α, and HIF-1α in curcumin-treated cells. Network pharmacology was used to predict the metabolic pathways, and the results were validated by Western blotting. In a nude mouse model bearing A549 cell xenograft, the effects of curcumin (20 mg/kg) on tumor growth and lipid metabolism were assessed by measuring tumor weight and observing the changes in intracellular lipid droplets. RESULTS:Curcumin concentration-dependently inhibited the proliferation of A549 and H1299 cells and significantly reduced TG and NEFA levels and intracellular lipid droplets. Western blotting revealed that curcumin significantly upregulated PGC-1α and PPAR‑α expressions in the cells. KEGG pathway enrichment analysis predicted significant involvement of the HIF-1 signaling pathway in curcumin-treated NSCLC, suggesting a potential interaction between HIF-1α and PPAR‑α. Western blotting confirmed that curcumin downregulated the expression of HIF-1α. In the tumor-bearing mice, curcumin treatment caused significant reduction of the tumor weight and the number of lipid droplets in the tumor cells. CONCLUSIONS:Curcumin inhibits NSCLC cell proliferation and lipid metabolism by downregulating the HIF-1α pathway.

Cancer is one of the major diseases threatening human health. Traditional drug often shows poor delivery and unsatisfactory therapy efficacy, while as a novel treatment modality, targeted therapy brings hope for malignant tumor. Targeted cancer therapy enables drugs to precisely target cancer cells by identifying and targeting molecular markers (such as proteins or gene mutations) specific to cancer cells, while minimizing damage to normal cells. The rapid development of nanotechnology has provided strong support for the development of tumor-specific targeted nanomedicine systems. Micro/nanomotor (MNM) is regarded as a promising candidate for the development of efficient target delivery and therapeutic system, due to their flexible energy input for drug loading and releasing. In the biomedical field, researchers have continuously tried to develop a variety of MNMs for targeted cancer therapy and have made some progress. Herein, we reviewed the development history of MNMs and detailed their kinetic mechanisms. Subsequently, to facilitate the preparation of MNMs, we summarized the synthesis methods of different types of MNMs. Finally, we highlighted the progress of MNMs in drug delivery for regulating tumor immune microenvironment and overcoming physiological barriers.

Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress.

Cancer immunotherapy, which leverages the body's immune system to combat cancer, offers the promise of lower toxicity and higher therapeutic efficacy compared to conventional treatments. However, current immunotherapeutic approaches face significant challenges including variable patient response, immune‐related adverse events, and high costs, underscoring the urgent need for innovative strategies. Metal‐based nanomaterials have emerged as a promising avenue in cancer immunotherapy due to their unique physicochemical properties and immune‐regulating capabilities. Despite their potential, concerns about toxicity, incomplete understanding of their immune modulation mechanisms, and early‐stage design strategies hinder their clinical translation. This review summarizes recent advancements in metal‐based nanomaterials for cancer immunotherapy, elucidates the mechanisms by which they enhance antitumor immunity responses, and explores the potential synergistic effects of combining multiple metals. We also discuss key challenges and future perspectives for clinical application, aiming to provide a theoretical foundation for the development of metal‐based immunotherapies and to promote their broader application in cancer treatment.

Piezoelectric sonodynamic therapy (SDT) is a novel non-invasive and highly penetrating cancer treatment method, which can be triggered by ultrasound (US) to induce energy band tilting of piezoelectric sonosensitizers to promote the generation of reactive oxygen species (ROS). However, it remains a challenge to modulate the energy band structure of piezoelectric sonosensitizers to overcome the energy barriers for efficient ROS production at limited US power. Here, Na0.5Bi0.5TiO3 clad with platinum (NBT@Pt) is designed through interface engineering to enhance its piezoelectric properties by leveraging the built-in electric field created between the noble metal Pt and the centrosymmetric semiconductor NBT, thereby breaking the inversion symmetry of the material. Meanwhile, O2 can be generated from the decomposition of H2O2, catalyzed by Pt NPs in the tumor microenvironment, which increases the cavitation strength by 143.5%, resulting in higher piezoelectric potential and piezoelectric catalytic performance of NBT@Pt. Cellular and animal experiments show that NBT@Pt has good biocompatibility and high antitumor efficiency, which show the high tumor inhibition rate as 92.8%. In this study, a novel modulation strategy of piezoelectric sonosensitizers is developed, which provides a typical example for the development of piezoelectric sonosensitizers in the field of anti-tumor therapy.

Singlet oxygen (1O2), an excellent reactive oxygen species (ROS) for tumor therapy, has garnered significant attention recently. However, its production is hindered by the low oxygen content in solid tumors characterized by hypoxia. Consequently, it is urgent to develop an O2-independent generator. In this study, we present a novel nano-assembly composed of manganese (III) phthalocyanine complex (MnClPc) encapsulated by human serum albumin (MnClPc@HSA). MnClPc@HSA serves as a conventional sonosensitizer, facilitating the conversion of O2 to 1O2 under ultrasonic stimulation (US). Moreover, MnClPc@HSA enables the conversion of endogenous hydrogen peroxide (H2O2) within tumor to superoxide radical (center dot O2-) and 1O2 and further enhanced by US. This O2-independent generation of multiple ROS by MnClPc@HSA overcomes the limitations imposed by tumor hypoxia, while inducing immunogenic cell death (ICD) and enhancing the infiltration of T cells as well. When combined with conventional PD-L1 immunotherapy, this approach effectively inhibits the proliferation of distal and lung-metastatic tumors, while concurrently eliminating primary tumors in the bilateral-tumor model of 4 T1 tumor-bearing mice.

[This corrects the article DOI: 10.3389/fonc.2021.617787.].