Metal-Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells.

Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal-organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells' membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating •O2-, and the Cu-THBQ/AX catalyzes O2 and H2O2 to •O2- and •OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of •OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from "cold" to "hot" conditions, making it an effective antigen pool. This transformation successfully activates the antitumor immune response, inhibiting tumor growth and metastasis.

Behavioral evidence of impaired self-referential processing in patients with affective disorders and first-episode schizophrenia.

Despite the critical role of self-disturbance in psychiatric diagnosis and treatment, its diverse behavioral manifestations remain poorly understood. This investigation aimed to elucidate unique patterns of self-referential processing in affective disorders and first-episode schizophrenia. A total of 156 participants (41 first-episode schizophrenia [SZ], 33 bipolar disorder [BD], 44 major depressive disorder [MDD], and 38 healthy controls [HC]) engaged in a self-referential effect (SRE) task, assessing trait adjectives for self-descriptiveness, applicability to mother, or others, followed by an unexpected recognition test. All groups displayed preferential self- and mother-referential processing with no significant differences in recognition scores. However, MDD patients showed significantly enhanced self-referential recognition scores and increased bias compared to HC, first-episode SZ, and BD. The present study provides empirical evidence for increased self-focus in MDD and demonstrates that first-episode SZ and BD patients maintain intact self-referential processing abilities. These findings refine our understanding of self-referential processing impairments across psychiatric conditions, suggesting that it could serve as a supplementary measure for assessing treatment response in first-episode SZ and potentially function as a discriminative diagnostic criterion between MDD and BD.

Triphenylamine[3]arenes: Streamlining Synthesis of a Versatile Macrocyclic Platform for Supramolecular Architectures and Functionalities.

Triphenylamine[3]arenes (TPA[3]s), featuring [16]paracyclophane backbone with alternating carbon and nitrogen bridging atoms, were synthesized through a BF3·Et2O-catalyzed cyclization reaction using triphenylamine derivatized monomers and paraformaldehyde. This molecular design yielded a series of TPA[3] macrocycles with high efficiency, with their facile derivatizations also successfully demonstrated. On account of the strong electron-donating properties of the TPA moieties, these TPA[3]s exhibit remarkable delayed fluorescence, and possess a significant affinity for iodine. Furthermore, their inherent three-fold symmetry rendered TPA[3]s as novel building blocks for the construction of extended frameworks and molecular cages. This advancement expands the versatility of discrete macrocycles into complex architectures, enhancing their applicability across a broad spectrum of applications.

Microenvironment-sensitive nanozymes for tissue regeneration.

Tissue defect is one of the significant challenges encountered in clinical practice. Nanomaterials, including nanoparticles, nanofibers, and metal-organic frameworks, have demonstrated an extensive potential in tissue regeneration, offering a promising avenue for future clinical applications. Nonetheless, the intricate landscape of the inflammatory tissue microenvironment has engendered challenges to the efficacy of nanomaterial-based therapies. This quandary has spurred researchers to pivot towards advanced nanotechnological remedies for overcoming these therapeutic constraints. Among these solutions, microenvironment-sensitive nanozymes have emerged as a compelling instrument with the capacity to reshape the tissue microenvironment and enhance the intricate process of tissue regeneration. In this review, we summarize the microenvironmental characteristics of damaged tissues, offer insights into the rationale guiding the design and engineering of microenvironment-sensitive nanozymes, and explore the underlying mechanisms that underpin these nanozymes' responsiveness. This analysis includes their roles in orchestrating cellular signaling, modulating immune responses, and promoting the delicate process of tissue remodeling. Furthermore, we discuss the diverse applications of microenvironment-sensitive nanozymes in tissue regeneration, including bone, soft tissue, and cartilage regeneration. Finally, we shed our sights on envisioning the forthcoming milestones in this field, prospecting a future where microenvironment-sensitive nanozymes contribute significantly to the development of tissue regeneration and improved clinical outcomes.

CD74 as a prognostic and M1 macrophage infiltration marker in a comprehensive pan-cancer analysis.

CD74 is a type-II transmembrane glycoprotein that has been linked to tumorigenesis. However, this association was based only on phenotypic studies, and, to date, no in-depth mechanistic studies have been conducted. In this study, combined with a multi-omics study, CD74 levels were significantly upregulated in most cancers relative to normal tissues and were found to be predictive of prognosis. Elevated CD74 expression was associated with reduced levels of mismatch-repair genes and homologous repair gene signatures in over 10 tumor types. Multiple fluorescence staining and bulk, spatial, single-cell transcriptional analyses indicated its potential as a marker for M1 macrophage infiltration in pan-cancer. In addition, CD74 expression was higher in BRCA patients responsive to conventional chemotherapy and was able to predict the prognosis of these patients. Potential CD74-activating drugs (HNHA and BRD-K55186349) were identified through molecular docking to CD74. The findings indicate activation of CD74 may have potential in tumor immunotherapy.

Crystalline Olefin-Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis.

The construction of olefin-linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self-healing process. Herein, we successfully synthesized two sets of enantiomeric olefin-linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as-prepared (R)/(S)-CCOF8 exhibits excellent catalytic performance with exceeding 99% enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Relationship between ruminative style and adolescent depression.

BACKGROUND: The role of rumination in depression remains controversial. We aimed to establish the ruminative tendency style theory (RTST), discuss the occurrence of depression in adolescents with rumination as the core, and explore the different associations between adolescent ruminative tendency, ruminative style, and depression. METHODS: This study employed an online questionnaire survey of 1110 Chinese adolescents aged 12-17 years, assessing ruminative tendency, ruminative style, stressful life events, depressive state, depressive trait, the Big Five personality traits, and social support. Conditional process analysis was used to test the chain mediation effect with Ruminative Style as a moderator. After screening for the predictor variables, a logistic regression risk prediction model was established and validated internally. RESULTS: The chain mediation effect of ruminative tendency and depressive trait between stressful life events and depressive state was significant, with the indirect effect accounting for 63.4%. Ruminative Style negatively moderated the relationship between Ruminative Tendency and Depressive Trait (ß=-0.053，P＜0.001). The risk prediction model for depressive state showed good calibration and clinical utility. Area under the curve values for the validation and training sets were 0.926 and 0.927, respectively. CONCLUSION: Different associations may exist between adolescent ruminative tendency, ruminative style, and depression, and the proposal of ruminative style is of great significance for intervention in adolescent depression.

Activable Nano-Immunomodulator Assembled from π-Extended Naphthalenediimide for Precision Photothermal Immunotherapy.

A nano-immunomodulator (R-NPT NP) comprising a tumor microenvironment (TME) activable resiquimod (R848) and a π-extended NIR-absorbing naphthophenanthrolinetetraone (NPT) has been engineered for spatiotemporal controlled photothermal immunotherapy. R-NPT NP demonstrated excellent photostability, while R848 promoted synergistic immunity as a toll-like receptor 7/8 (TLR7/8) agonist. Upon accumulation at the tumor site, R-NPT NP released R848 in response to redox metabolite glutathione (GSH), triggering dendritic cell (DC) activation. The photothermal effect endowed by R-NPT NP can ablate tumors directly and trigger immunogenic cell death to augment immunity after photoirradiation. The synergistic effect of GSH-liable TLR7/8 agonist and released immunogenic factors leads to a robust evocation of systematic immunity through promoted DC maturation and T cell infiltration. Thus, R-NPT NP with photoirradiation achieved 99.3 % and 98.2 % growth inhibition against primary and distal tumors, respectively.

Brain stimulation over the left DLPFC enhances motivation for effortful rewards in patients with major depressive disorder.

BACKGROUND: Amotivation is a typical feature in major depressive disorder (MDD), which produces reduced willingness to exert effort. The dorsolateral prefrontal cortex (DLPFC) is a crucial structure in goal-directed actions and therefore is a potential target in modulating effortful motivation. However, it remains unclear whether the intervention is effective for patients with MDD. METHODS: We employed transcranial magnetic stimulation (TMS), computational modelling and event-related potentials (ERPs) to reveal the causal relationship between the left DLPFC and motivation for effortful rewards in MDD. Fifty patients underwent both active and sham TMS sessions, each followed by performing an Effort-Expenditure for Rewards Task, during which participants chose and implemented between low-effort/low-reward and high-effort/high-reward options. RESULTS: The patients showed increased willingness to exert effort for rewards during the DLPFC facilitated session, compared with the sham session. They also had a trend in larger P3 amplitude for motivated attention toward chosen options, larger CNV during preparing for effort exertion, and larger SPN during anticipating a high reward. Besides, while behavior indexes for effortful choices were negatively related to depression severity in the sham session, this correlation was weakened in the active stimulation session. CONCLUSIONS: These findings provide behavioral, computational, and neural evidence for the left DLPFC on effortful motivation for rewards. Facilitated DLPFC improves motor preparation and value anticipation after making decisions especially for highly effortful rewards in MDD. Facilitated DLPFC also has a potential function in enhancing motivated attention during cost-benefit trade-off. This neuromodulation effect provides a potential treatment for improving motivation in clinics.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Strong Interactions between Au Nanoparticles and BiVO4 Photoanode Boosts Hole Extraction for Photoelectrochemical Water Splitting.

Strong metal-support interaction (SMSI) is widely proposed as a key factor in tuning catalytic performances. Herein, the classical SMSI between Au nanoparticles (NPs) and BiVO4 (BVO) supports (Au/BVO-SMSI) is discovered and used innovatively for photoelectrochemical (PEC) water splitting. Owing to the SMSI, the electrons transfer from V4+ to Au NPs, leading to the formation of electron-rich Au species (Auδ-) and strong electronic interaction (i.e., Auδ--Ov-V4+), which readily contributes to extract photogenerated holes and promote charge separation. Benefitted from the SMSI effect, the as-prepared Au/BVO-SMSI photoanode exhibits a superior photocurrent density of 6.25 mA cm-2 at 1.23 V versus the reversible hydrogen electrode after the deposition of FeOOH/NiOOH cocatalysts. This work provides a pioneering view for extending SMSI effect to bimetal oxide supports for PEC water splitting, and guides the interfacial electronic and geometric structure modulation of photoanodes consisting of metal NPs and reducible oxides for improved solar energy conversion efficiency.

Association of handgrip strength asymmetry and weakness with functional disability among middle-aged and older adults in China.

Background: Little is known about the association of handgrip strength (HGS) asymmetry with functional disability in China. We aimed to examine the individual and combined association of HGS asymmetry and weakness with functional disability among middle-aged and older Chinese adults. Methods: We included participants aged ≥45 years from two waves of the China Health and Retirement Longitudinal Study (2011 and 2015). HGS weakness was defined as the maximal HGS<28 kg for men and <18 kg for women. HGS asymmetry was measured by dividing the maximal nondominant HGS (kg) by the maximal dominant HGS (kg), with the value <0.90 or >1.10 considered as asymmetry. Functional disability was assessed by activities of daily living (ADL) and instrumental activities of daily living (IADL) and was defined as encountering difficulty in completing one or more ADL/IADL tasks. The logistic regression models were used to explore the association between HGS measures and functional disability. Results: 11 950 (mean age 59.2 ± 9.6 years, 47.9% males) and 7540 (mean age 57.5 ± 8.6 years, 50.1% males) participants were included in the cross-sectional and prospective study, respectively. HGS asymmetry and weakness, individually or simultaneously, were associated with an increased prevalence of functional disability. During the four-year follow-up, 1822 (24.2%) participants had incident functional disability. The separate exposure to HGS asymmetry (odds ratio (OR) = 1.18; 95% confidence interval (CI) = 1.05-1.32) or weakness (OR = 1.59; 95% CI = 1.30-1.95) was independently associated with functional disability. For combined associations, those with both weakness and asymmetry showed the greatest risk of new-onset functional disability (OR = 1.91; 95% CI = 1.45-2.52). Conclusions: HGS asymmetry and weakness were associated with a higher risk of functional disability. Assessing HGS asymmetry together with weakness may help to better identify those at risk of functional disability to enable early interventions.

Effects of Dietary Selenium Yeast Supplementation on Lactation Performance, Antioxidant Status, and Immune Responses in Lactating Donkeys.

Donkey milk is a traditional medicinal food with various biological activities. However, its production is very low, and lactating donkeys often experience oxidative stress, leading to a further decline in milk yield. In this study, we supplemented the diets of lactating donkeys with yeast selenium (SY) to investigate its effects on lactation performance, antioxidant status, and immune responses, and we expected to determine the optimum additive level of SY in the diet. For this study, 28 healthy lactating Dezhou donkeys with days in milk (DIM, 39.93 ± 7.02 d), estimated milk yield (EMY, 3.60 ± 0.84 kg/d), and parity (2.82 ± 0.48) were selected and randomly divided into 4 groups of 7 donkeys in each: Group SY-0 (control), Group SY-0.15, Group SY-0.3, and Group SY-0.5, with selenium supplementation of 0, 0.15, 0.3, and 0.5 mg of Se/kg DM (in form of SY) to the basal diet, respectively. The results showed a dose-dependent increase in milk yield, milk component yield, milk protein production efficiency, milk production efficiency, the activities of glutathione peroxidases (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), as well as the content of serum interleukin-10 (IL-10), white blood cells (WBC), lymphocytes (LYM), red blood cells (RBC), hematocrit, plasma selenium, and milk selenium. Conversely, it presented a dose-dependent decrease in the activity of nitric oxide synthase (iNOS) and the contents of malondialdehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interferon-γ (IFN-γ). In conclusion, the results confirmed that dietary supplementation with SY can improve lactation performance, antioxidant status, and immune responses in lactating donkeys, and the recommended dose of SY was 0.3 mg/kg.

A Cancer Nanovaccine Based on an FeAl-Layered Double Hydroxide Framework for Reactive Oxygen Species-Augmented Metalloimmunotherapy.

The complexity and heterogeneity of individual tumors have hindered the efficacy of existing therapeutic cancer vaccines, sparking intensive interest in the development of more effective in situ vaccines. Herein, we introduce a cancer nanovaccine for reactive oxygen species-augmented metalloimmunotherapy in which FeAl-layered double hydroxide (LDH) is used as a delivery vehicle with dihydroartemisinin (DHA) as cargo. The LDH framework is acid-labile and can be degraded in the tumor microenvironment, releasing iron ions, aluminum ions, and DHA. The iron ions contribute to aggravated intratumoral oxidative stress injury by the synergistic Fenton reaction and DHA activation, causing apoptosis, ferroptosis, and immunogenic cell death in cancer cells. The subsequently released tumor-associated antigens with the aluminum adjuvant form a cancer nanovaccine to generate robust and long-term immune responses against cancer recurrence and metastasis. Moreover, Fe ion-enabled T1-weighted magnetic resonance imaging can facilitate real-time tumor therapy monitoring. This cancer-nanovaccine-mediated metalloimmunotherapy strategy has the potential for revolutionizing the precision immunotherapy landscape.

Study of Microstructure and Performance Evaluation of Zr-Sn-Nb Joints by Electron Beam Welding.

In this work, Zr-Sn-Nb alloy was joined by electron beam welding (EBW). A defect-free Zr-Sn-Nb joint with sound appearance was obtained. The grains in the weld zone (WZ) and heat-affected zone (HAZ) are significantly coarsened. The columnar grains with a maximum grain size of 0.5 mm are distributed in the upper region of the WZ, while the equiaxed grains are almost located in the bottom region of the WZ. The WZ is mainly composed of the dominant α-Zr, α'-Zr and a few ß phases. The grain orientation of WZ and HAZ is uniform, indicating that no obvious preferred orientation existed. Coarse grains and fine acicular α' phases increase the strength of the joint, but reduce the plasticity and toughness of the joint. The tensile strengths of the joints at room temperature (RT) and 375 °C were 438 MPa and 313 MPa, respectively. The RT impact energy of the joint is 18.5 J, which is only 58.3% of the BM. The high purity of the EBW process and unsignificant grain orientation minimizes damage to the corrosion resistance of Zr-Sn-Nb alloy joints. The corrosion weight gain of the joint specimen and the BM specimen were 12.91 mg/dm2 and 12.64 mg/dm2, respectively, and the thicknesses of the cross-section corrosion layer were 12-15 µm and 9-12 µm, respectively.

Effects of Hydrogenation on the Corrosion Behavior of Zircaloy-4.

Hydrogen plays an important role in the corrosion of zirconium alloys, and the degree of influence highly depends on the alloy composition and conditions. In this work, the effects of hydrogenation on the corrosion behavior of Zircaloy-4 in water containing 3.5 ppm Li + 1000 ppm B at 360 °C/18.6 MPa were investigated. The results revealed that hydrogenation can shorten the corrosion transition time and increase the corrosion rates of Zircaloy-4. The higher corrosion rates can be ascribed to the larger stress in the oxide film of hydrogenated samples, which can accelerate the evolution of the microstructure of the oxide film. In addition, we also found that hydrogenation has little effect on the t-ZrO2 content in the oxide film and there is no direct correspondence between the t-ZrO2 content and the corrosion resistance of the Zircaloy-4.

Efficient chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle as "in situ" vaccine integrated tumor ICD and immunoagonist.

INTRODUCTION: Immunotherapy has unprecedentedly opened up a series of neoteric tactics for cancer treatment. As a burgeoning approach, chemo-immunotherapy has innovatively expanded the accomplishments of conventional chemotherapeutic agents for cancer governing. OBJECTIVES: An efficacious chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle (NP) integrated tumor immunogenic cell death (ICD) and immunoagonist was developed as a watertight "in situ" vaccine for cancer therapy through convenient intratumoral administration with minimized systemic toxicity. METHODS: Chemical-modified pH-sensitive cis-aconityl-doxorubicin (CAD) and immunoadjuvant unmethylated cytosine-phosphate-guanine (CpG) were co-packaged by polycationic polyethylenimine (PEI) though electrostatic-interaction to construct PEI/CpG/CAD NP. By intratumoral injection, this positively charged NP could be detained at tumor site and endocytosed by tumor cells effortlessly. Then, doxorubicin was released through cis-aconityl cleavage induced by endosomal-acidity and further triggered tumor ICD, the moribund tumor cells could release damage-associated molecular patterns (DAMPs) to recruit dendritic cells (DCs). Meanwhile, the entire tumor debris derived into diversified antigens and cooperated with immunostimulatory CpG to excite DC maturation and activated comprehensive antitumor immunity. RESULTS: Prominent tumor suppression was achieved in aggressive mouse melanoma tumor model, which verified the feasibility and effectiveness of this minimalist CAD/CpG-codelivered NP. CONCLUSION: This study has provided a convenient and promising paradigm for potent cancer chemo-immunotherapy.

Discovery of Selective and Potent ATR Degrader for Exploration its Kinase-Independent Functions in Acute Myeloid Leukemia Cells.

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.

In Situ Mitochondrial Biomineralization for Drug-Free Cancer Therapy.

The common clinical chemotherapy often brings serious side effects to patients, mainly due to the off-target and leakage of toxic drugs. However, this is fatal for some specific clinical tumors, such as brain tumors and neuroma. This study performs a drug-free approach by encapsulating black phosphorus (BP) and calcium peroxide (CaO2) in liposomes with surface-modified triphenylphosphonium (BCLT) to develop mitochondria targeting calcification for cancer therapy without damaging normal cells. BCLT preferentially accumulates inside tumor mitochondria and then is activated by near-infrared (NIR) laser irradiation to produce abundant PO4 3- and Ca2+ to accelerate in situ mitochondrial mineralization, leading to mitochondrial dysfunction and cancer cell death. More importantly, both PO4 3- and Ca2+ are essential components of metabolism in the body, and random gradient diffusion or premature leakage does not cause damage to adjacent normal cells. This achievement promises to be an alternative to conventional chemotherapy in clinical practice for many specific tumor types.