The fat mass and obesity-associated protein (FTO), a pivotal eraser of N6-methyladenosine (m6A) modifications, has emerged as a critical biomarker and therapeutic target in tumorigenesis. However, the accurate assessment of FTO activity in biological settings remains challenging due to limitations in sensitivity and cellular compatibility of existing methods. Herein, we develop an enzyme-free DNA circuit that integrates m6A-directed deoxyribozyme (DNAzyme) activation with autocatalytic hybridization assembly (AHA) for the sensitive monitoring of demethylase activity. In this system, FTO-mediated demethylation triggers the DNAzyme, which via a docking hairpin, transduces the recognition event into a cross-catalytic hybridization chain reaction (HCR)-catalytic hairpin assembly (CHA) circuit, thereby generating exponential signal amplification. This biosensing platform achieves an exceptional detection limit of 22.6 pM and is successfully applied to the screening of FTO inhibitors. Furthermore, the platform demonstrates the capability to reliably discriminate between cancer cells and normal cells based on distinct fluorescence signals. As a robust and entirely nucleic acid-based programmable strategy, this method provides a versatile and powerful tool for advancing epigenetic research and point-of-care molecular diagnostics.

Lysosomal membrane permeabilization (LMP) mediated by pH-responsive materials has demonstrated considerable potential in tumor therapy. However, tumor cells exhibit a pronounced adaptive capacity to remodel lysosomal pH, thereby resisting LMP induction by pH-responsive materials and ultimately compromising therapeutic efficacy. To overcome this limitation, we engineered proton-driven π-π stacked copper-phycocyanin nanoparticles (CuPC NPs) designed to selectively promote LMP in tumor cells through their aggregation within acidic lysosomes. Mechanistically, aggregated CuPC NPs directly engage the RIPK3/p-MLKL signaling axis to trigger LMP, thereby orchestrating the synergistic activation of necroptosis, ferroptosis, and cuproptosis. Due to the coordinated induction of multimodal cell death, these pH-responsive CuPC NPs effectively inhibit primary breast tumor growth and suppress pulmonary metastasis. Collectively, our study establishes a strategy for precise modulation of lysosomal function to enhance antitumor efficacy and provides valuable insights into the development of lysosome-targeted nanotherapeutics for tumor treatment.

Simultaneously restricting bacterial proliferation, mitigating inflammatory reactions and excessive reactive oxygen species (ROS)-mediated corneal damage during sleep represents a crucial therapeutic strategy for managing bacterial keratitis (BK).

Immune-mediated graft rejection (IMGR) remains a leading cause of corneal transplant (CT) failure in high-risk cases. While transcorneal delivery of tacrolimus (FK506) is a promising strategy, the cornea’s barrier properties severely limit FK506′s bioavailability and therapeutic function. Here, we developed a transcorneal delivery system by loading FK506 into zeolitic imidazolate framework-8 (ZIF-8) to form the FK506@ZIF-8 nanoparticles (<100 nm) with 4.5 % drug-loading capacity, followed by mixing with 2-hydroxypropyltrimethyl ammonium chloride chitosan (HTCC) solution to form a homogeneous sol. In vitro studies demonstrated sustained FK506 release over 24 h of the FK506@ZIF-8 in a simulated ocular microenvironment via ZIF-8 framework hydrolysis (Weibull model) and confirmed its biosafety in human corneal epithelial cells (HCECs) at concentrations ≤ 20 μg/mL. The Draize test validated minimal ocular irritation of the FK506@ZIF-8/HTCC eye drop in rabbits. The nano-size of the FK506@ZIF-8 combined with the HTCC-mediated corneal adhesion (>240 min retention) synergistically enhanced transcorneal delivery of FK506. In a rabbit IMGR model, the FK506@ZIF-8/HTCC eye drop significantly prolonged graft survival, reduced inflammatory infiltration, and outperformed conventional FK506 eye drops, highlighting its therapeutic potential for overcoming corneal drug delivery barriers. In summary, the FK506@ZIF-8/HTCC sol hold great promise for preventing high-risk keratoplasty rejection in clinic in the future.

Achilles tendinitis (AT) has posed as an intractable clinical problem, for which there is currently a lack of satisfactory treatment approaches. Local drug delivery has proven to be effective for AT therapy, but suitable drugs and local/sustained drug delivery technique for superior therapeutic effects are still in urgent need. In this work, screw-thread needle acupuncture-mediated in situ delivery of tangeretin@β-cyclodextrin sulfated sodium salt (TAN@CDs) complexes was developed for AT therapy. Briefly, TAN was firstly encapsulated into the cavity of CDs with a TAN loading rate of 4.6%. Then, a trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride-modified screw-thread needle (TMSTN) was immersed into the TAN@CDs solution to fasten the TAN@CDs complexes to the grooves of the TMSTN through electrostatic interaction. The biosafe concentration of TAN@CDs solution was controlled at 30 mg/mL through hemolysis assay, H&E staining, and blood biochemical analyses. TAN@CDs could release TAN in a sustained manner for over 8 h in a simulated Achilles tendon microenvironment. TAN delivery amount of single acupuncture (sequential clockwise/anticlockwise rotation) of the TAN@CDs/TMSTN was determined to be 1.28 μg, and an Achilles tendon defect model of rat was applied to evaluate its therapeutic effects against AT. Gross appearance observation of the Achilles tendon, H&E staining, Masson staining, and biomechanical testing proved that through periodic acupuncture of the TAN@CDs/TMSTN, AT could nearly be cured. The superior therapeutic outcomes of TAN@CDs/TMSTN‑mediated acupuncture against AT are likely attributable to the synergistic interplay between the acupuncture intervention and the in situ release of TAN. Immunohistochemical staining demonstrated that the released TAN molecules treat AT through downregulating inflammatory cytokines and upregulating tendon repair-related factors, therefore promoting collagen synthesis and tenogenic differentiation throughout healing. In sum, this work reported an efficient strategy for AT therapy.

Tendinopathy markedly impairs patients' quality of life, yet effective therapies remain limited. Conventional therapeutic strategies have largely overlooked the pivotal role of macrophages (Mφ) and Mφ-mediated immunoregulation in this condition. To address this, we designed a microneedle patch (MP) for the in situ delivery of rosmarinic acid (RosA), aiming to modulate local Mφ phenotype. We evaluated the therapeutic efficacy of this RosA-MP against tendinopathy and investigated the underlying mechanism. Briefly, the RosA-MP was fabricated by incorporating RosA into a microneedle array composed of poly(hydroxyethyl methacrylate-co-3-acrylamidophenyl boronic acid-co-(3-methacrylamidopropyl)trimethylammonium chloride) [poly(HEMA-co-3APBA-co-MAPTAC)], which was covalently linked to a flexible filter paper matrix. Formation of phenylboronic acid ester bonds between the 3APBA moieties and RosA endowed the RosA-MP with enhanced stiffness and skin penetration capability, facilitating sustained RosA release. Furthermore, the MAPTAC moieties provided instant hydrophilic swelling upon skin insertion, accelerating RosA delivery via increased internal osmotic pressure. In vitro and in vivo assays demonstrated that the RosA-MP simultaneously induced in situ M2 Mφ polarization and scavenged reactive oxygen species. Mechanistic investigation revealed that suppression of the NLRP3 inflammasome contributed to the rationale behind Mφ polarization. Using a collagenase type I-induced rat tendinopathy model, we assessed the therapeutic effects of the RosA-MP. Results confirmed that the RosA-MP effectively treated tendinopathy and exhibited significant advantages over injection therapy.

As emerging biopolymer materials, DNA hydrogels quickly respond to external stimuli to specifically recognize DNA through base pairing and have become widely used in the field of biosensors. Unlike traditional biosensing strategies, biosensors based on DNA hydrogels are highly specific, programmable and degradable. In this work, based on the advantages and wide application of DNA hydrogels in the field of biosensors, the progress of DNA hydrogel biosensors is systematically summarized in terms of the types of DNA hydrogels, detection principles and biosensor device integration. First, the types of DNA hydrogels used in biosensors are briefly introduced. Next, we thoroughly demonstrate the detection principles of DNA hydrogel biosensors; the detection principles depend on the recognition elements, signal elements, and transduction types of the DNA hydrogel used in the biosensor. In particular, we demonstrate the great potential of integrated devices and techniques used in DNA hydrogel biosensors, such as microfluidics and portable devices. Finally, the challenges and future development of DNA hydrogels in biosensing are discussed. This work can be used as a reference for research on biosensing analysis using DNA hydrogels.

MicroRNAs (miRNAs) are increasingly recognized as vital biomarkers for cancer, given their aberrant expression patterns in oncogenesis. Sensitive detection of these miRNAs is imperative for early-stage cancer diagnostics. Current fluorescence-based assays, while effective, are limited by the need for costly labeling and external laser sources, contributing to elevated autofluorescence background signals. Our study introduces a label- and laser-free, chemiluminescence-based, autocatalytic DNA circuit composed of catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR), offering a sensitive and accurate approach to miRNA detection. The target T initiates CHA, generating multiple dsDNA products with exposed initiator I sequences. I triggers HCR to form long nanowires encoded with intact T and hemin/G-quadruplex DNAzyme structures, respectively, leading to self-catalytic cycles and amplified chemiluminescence signal output. By integrating auxiliary recognition hairpin, this autocatalytic chemiluminescence method enables the sensitive detection of miRNA. Overall, our sensitive and accurate miRNA assay provides a novel tool for the early diagnosis of cancer.

AIM: To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma (POAG) based on a Mendelian randomization (MR) study. METHODS: Large-scale protein quantitative trait loci (pQTLs) data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study (GWAS) summary datasets were used in this study. Causal associations between plasma proteins and POAG were identified using summary-data-based MR (SMR) analysis and the heterogeneity in dependent instruments (HEIDI) test. Colocalization analysis was then conducted to assess the genetic associations between these two factors. Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects. Finally, protein-protein interactions (PPI) were studied, and the Drug-Gene Interaction Database (DGIDb) was used to identify associations between drugs and the identified proteins. RESULTS: Four proteins (SVEP1, TMEM190, ROBO1, and ENPP5) were identified as potential drug targets in this study. Phenome-wide MR analysis showed that SVEP1, ROBO1, and ENPP5 were not associated with adverse effects, while TMEM190 was linked to nerve root and plexus disorders, as well as subarachnoid hemorrhage. Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1. CONCLUSION: Four plasma proteins—SVEP1, TMEM190, ROBO1, and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach. Phenome-wide MR analysis reveals that SVEP1, ROBO1, and ENPP5 are not associated with adverse effects, while TMEM190 is linked to nerve root and plexus disorders, as well as subarachnoid hemorrhage. Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1. These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.

Methylation modification is a critical regulatory mechanism in epigenetics and plays a significant role in various biological processes. N6-methyladenosine (m6A) is the most common modification found in RNA. The fat mass and obesity-associated protein (FTO) facilitate the demethylation of m6A in RNA, and its abnormal expression is closely linked to the development of several diseases. As a result, FTO has the potential to serve as an important biomarker for clinical disease diagnosis. Despite its significance, there has been a lack of comprehensive reviews addressing advancements in detection methods for the demethylase FTO. This review provides an overview of the progress in FTO detection methods, ranging from traditional approaches to innovative techniques, with a particular emphasis on recently reported advancements. These novel detection methods can be categorized into strategies based on enzymes, functional nucleic acids (FNA), and conformational changes. We summarize the principles and applications of these detection methods and discuss the current challenges and prospects in this field.

Developing advanced technologies for the consolidation and shaping of rotten/pulverized silk fabrics (RPSFs) is of vital historical and cultural value, but currently reported strategies are still far from satisfactory. In this regard, a poly(ethylenimine)/poly(ethylene glycol) diglycidyl ether/isopropyl palmitate (PEI/PEGDE/IPP) method was proposed in this work. Briefly, a spatially adaptive three-dimensional (3D) cross-linked PEI/PEGDE framework was constructed around the silk fiber bundles of an RPSF to enhance its structural integrity, strength, toughness, and elasticity through successive soaking of the RPSF in an ethanol solution of branched PEI molecules and an acetone solution of PEGDE molecules. Then, IPP molecules were introduced into the PEI/PEGDE framework through soaking the PEI/PEGDE-treated RPSF in an ethanol solution of IPP molecules (1 wt %) to improve the softness and ductility of RPSF. Through three systematic orthogonal experiments (i.e., stiffness, chromaticity variation, and mechanical properties), the optimal initial feeding composition of PEI and PEGDE was screened and determined to be 2 and 2 wt %, respectively. A series of compositions and structural identifications indicated that the consolidation/shaping mechanism of the PEI/PEGDE/IPP method fitted with our initial theoretical assumption. Besides, the PEI/PEGDE/IPP treatment increased the ordered arrangement of the interchain domain and the fiber axis of RPSFs and, therefore, could enhance the antitearing capability of RPSF, which posed a positive influence on the long-term preservation of RPSFs. When being applied to true RPSF historical relics (Han Dynasty), the PEI/PEGDE/IPP treatment did not change their morphology, geometry, color, and texture but could improve the mechanical stability of RPSFs to some extent. Thus, the reported PEI/PEGDE/IPP method is promising for the preservation of RPSF historical relics in the future.

Functional injectable hydrogel (IH) is promising for infected bone defects (IBDs) repair, but how to endow it with desired antibacterial/immunoregulatory functions as well as avoid mechanical failures during its manipulation has posed as main challenges. Herein, rosmarinic acid (RosA), a natural product with antibacterial/immunoregulatory activities, was utilized to develop a FCR IH through forming phenylboronic acid ester bonds with 4-formylphenyl phenylboronic acid (4-FPBA) grafted chitosan (CS) (FC). After being applied to the IBD site, the FCR IH was then injected with tobramycin (Tob) solution, another alkaline antibacterial drug, to induce in situ crystallization of the FC, endowing the resultant FCRT hydrogel with adaptively enhanced mechanical strength and structural stability. Owing to the specific structural composition, the FCRT hydrogel could sustainedly release Tob and RosA molecules at the IBD interface, effectively eliminating in situ bacterial infection. In addition, the released RosA molecules also induced the M2 polarization of in situ macrophages (Mφ), which was identified to be related to the NF-κB and PI3K-AKT pathways, therefore promoting the osteogenic differentiation of in situ bone marrow stromal cells (BMSCs). Due to the simultaneous antibacterial/osteo-immunoregulatory microenvironment at the IBD interface, the repair of IBDs was proved to be greatly accelerated by the FCRT hydrogel.

Abstract Developing advanced technologies for consolidation and shaping of rotten/pulverized silk fabrics (RPSFs) is of vital historical and cultural values, but currently reported strategies are still far from satisfactory. In this regard, a novel PEI/PEGDE/IPP method was proposed in this work. Briefly, a spatially adaptive 3D cross-linked PEI/PEGDE framework was constructed around the silk fiber bundles of RPSF to enhance the structural integrity, strength, toughness, and elasticity of RPSF through successive soaking of RPSF in ethanol solution of branched poly(ethylenimine) (PEI) and acetone solution of poly(ethylene glycol) diglycidyl ether (PEGDE). Then, isopropyl palmitate (IPP) molecules were introduced into the PEI/PEGDE framework to improve the softness and ductility of RPSF. Through three systematic orthogonal experiments (i.e., stiffness, chromaticity variation, and mechanical properties), the optimal initial feeding composition of PEI and PEGDE were screened out and determined to be 2 wt% and 2 wt%, respectively. A series of composition and structural identification indicated that the consolidation/shaping mechanism of the PEI/PEGDE/IPP method fitted with our initial theoretical assumption. Besides, the PEI/PEGDE/IPP treatment induced ordered arrangement of RPSF along (210) crystal plane and, therefore, could enhance the anti-tearing capability of RPSF, which also positive influence on long-term preservation of RPSF. When being applied to true RPSF historical relics, the PEI/PEGDE/IPP method didn’t change its color and texture, and could improve the mechanical stability of RPSF to some extent. Thus, the reported PEI/PEGDE/IPP method is promising for preservation of RPSF historical relics in the future.

Injectable hydrogels (IHs) have demonstrated huge potential in promoting repair of infected bone defects (IBDs), but how to endow them with desired anti-bacterial, immunoregulatory, and osteo-inductive properties as well as avoid mechanical failure during their manipulation are challenging. In this regard, we developed a multifunctional AOHA-RA/Lap nanocomposite IH for IBDs repair, which was constructed mainly through two kinds of reversible cross-links: (i) the laponite (Lap) crystals mediated electrostatic interactions; (ii) the phenylboronic acid easter bonds between the 4-aminobenzeneboronic acid grafted oxidized hyaluronic acid (AOHA) and rosmarinic acid (RA). Due to the specific structural composition, the AOHA-RA/Lap IH demonstrated superior injectability, self-recoverability, spatial adaptation, and self-reinforced mechanical properties after being injected to the bone defect site. In addition, the RA molecules could be locally released from the hydrogel following a Weibull model for over 10 days. Systematic in vitro/vivo assays proved the strong anti-bacterial activity of the hydrogel against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Moreover, its capability of inducing M2 polarization of macrophages (Mφ) and osteogenic differentiation of bone marrow stromal cells (BMSCs) was verified either, and the mechanism of the former was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways and that of the latter was identified to be related to the calcium signaling pathway, extracellular matrix (ECM) receptor interaction and TGF-β signaling pathway. After being implanted to a S. aureus infected rat skull defect model, the AOHA-RA/Lap IH significantly accelerated repair of IBDs without causing significant systemic toxicity. STATEMENT OF SIGNIFICANCE: Rosmarinic acid and laponite were utilized to develop an injectable hydrogel, promising for accelerating repair of infected bone defects in clinic. The gelation of the hydrogel was completely driven by two kinds of reversible cross-links, which endow the hydrogel superior spatial adaption, self-recoverability, and structural stability. The as-prepared hydrogel demonstrated superior anti-bacterial/anti-biofilm activity and could induce M2 polarization of macrophages and osteogenic differentiation of BMSCs. The mechanism behind macrophages polarization was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways. The mechanism behind osteogenic differentiation of BMSCs was identified to be related to the ECM receptor interaction and calcium signaling/TGF-β signaling pathways.

As an acne sequela, post-acne scarring (PSA) has huge negative impact on sufferers’ quality of life because of aesthetical embarrassment. Transdermal delivery of botulinum toxin-A (BTXA) is a promising strategy for PAS treatment, but currently reported approaches are far from satisfactory. In this work, phosphatidylcholine/cholesterol (PC/Chol) nanoliposomes were utilized for encapsulation and transdermal delivery of BTXA. The composition, structure, morphology, size, size distribution, etc. of as-prepared BTXA@liposome nanoparticles were investigated in detail. Simulated transdermal delivery assay indicated that the diffusion depth of the BXTA@liposome nanoparticles was nearly 8 times that of pure BTXA and reached 380 μm. 12 facial PSA patients were recruited to evaluate the curative effect of the BTXA@liposome nanoparticles on PSA. Through ECCA (échelle d’évaluation clinique des cicatrices d’acné) scoring and self-evaluation of patients, the resultant data indicated that compared to hyaluronic acid (HA) hydrogel treatment the BTXA@liposome/HA hydrogel treatment could better relieve PSA to some extent but didn’t show significant advantage. Further work is needed to verify the feasibility and curative effect of this method in PSA treatment in the future.

Immunoregulation mediated bone tissue engineering (BTE) has demonstrated huge potential in promoting repair of critical-size bone defects (CSBDs). The trade-off between stable immunoregulation function and extended immunoregulation period has posed a great challenge to this strategy. Here, we reported a 3D porous biodegradable Poly(HEMA-co-3APBA)/LUT scaffold, in which reversible boronic acid ester bond was formed between the 3APBA moiety and the catechol moiety of luteolin (LUT). The boronic acid ester bond not only protected the bioactivity of LUT but also extended the release period of LUT. The rationale behind the phenomenon of sustained LUT release was explained using a classical transition state theory. In vitro/in vivo assays proved the immunoregulation function of the scaffold in inducing M2 polarization of both M0 and M1 Mφ. The crosstalk between the scaffold treated Raw 264.7 and BMSCs were also investigated through the in vitro co-culture assay. The results demonstrated that the scaffold could induce immunoregulation mediated osteogenic differentiation of BMSCs. In addition, CSBDs model of SD rats was also applied, and the corresponding data proved that the scaffold could accelerate new bone formation, therefore promoting repair of CSBDs. The as-prepared scaffold might be a promising candidate for repair of CSBDs in the future.

Regulating phenotypes of in situ macrophages (M phi) is a cutting-edge strategy for promoting bone-Titanium (Ti) integration, but what is the most rational modulation manner has long been controversial. Short-term inducing in situ M1 M phi polarization or inducing in situ M2 M phi polarization have proven to be capable of promoting osseointegration. However, an increasing number of researches have claimed that sequentially inducing in situ M1/M2 M phi polarization, compared to the above-mentioned two strategies, could further enhance osseointegration. In this work, we compared the capability of the three different modulation manners to promote osseointegration. Briefly, we anchored a homogeneous Poly(HEMA-co-3APBA)/LUT/SOP hydrogel coating, which could sequentially release pro-inflammatory sophoridine (SOP) molecules and anti-inflammatory luteolin (LUT) molecules through pH mediated conformational transition of phenylboronic acid ester bonds, on the surface of Ti implants. Ti implants coated with the Poly(HEMA-co-3APBA)/SOP hydrogel or the Poly(HEMA-co-3APBA)/LUT hydrogel, which merely released SOP molecules and LUT molecules respectively, were utilized as controls. In vitro M phi co-culture assays proved the immunoregulation functions of different hydrogel coatings in inducing M phi polarization, and the rationale behind which was identified to be related to the PI3K-AKT signaling pathways. In addition, the immunoregulation mediated osteogenic differentiation behaviors of bone marrow mesenchymal stem cells (BMSCs) were also investigated. Implantation of as-prepared Ti nails to a rat femur defect model followed by evaluations of H&E staining, Masson staining, immunohistochemical staining, etc. proved the stronger capability to enhance osseointegration of inducing sequential M1/M2 M phi polarization than short-term inducing in situ M1 M phi polarization or inducing in situ M2 M phi polarization. This work not only reported a novel Ti implant with superior osseointegration capability but also will inspire corresponding researches in the future.

Regarding carbon -based electrodes, simultaneously establishing a well-defined meso -porous architecture, introducing abundant hetero-atoms and improving the graphitization degree can effectively enhance their capacitive performance. However, it remains a significant challenge to achieve a good balance between defects and graphitization degree. In this study, the porous structure and composition of carbon materials are co -optimised through a 'dual -function ' strategy. Briefly, K 3 Fe(C 2 O 4 ) 3 and H 3 BO 3 were hybridised with a gelatin aqueous solution to form a homogeneous composite hydrogel, followed by lyophilisation and carbonisation. Owing to the dual functionality of raw materials, the graphitization, activation and hetero-atom doping processes can occur simultaneously during a one-step high -temperature treatment. The resultant carbon material exhibits a high graphitization degree (I D /I G = 0.9 +/- 0.1), high hetero-atom content (N: 9.0 +/- 0.3 at.%, B: 6.9 +/- 0.5 at.%) and a large specific area (1754 +/- 58 m 2 /g). The as -prepared electrode demonstrates a superior capacitance of 383 +/- 1F g - 1 at 1 A/g. Interestingly, the cyclic voltammetry (CV) curves exhibit a distinctive pair of broad redox peaks, which is uncommon in KOH electrolyte. Experiment data and density functional theory (DFT) simulation verify that N-5, B co -doping enhances the activity of the faradic reaction of carbon electrodes in KOH electrolyte. Furthermore, the fabricated Zn-ion hybrid supercapacitor (ZHSC) based on this carbon electrode delivers a highenergy density of 140.7 W h kg -1 at a power density of 840 W kg -1 .

The cross-talk between lysosomes and mitochondria is crucial for keeping intracellular homeostasis and metabolic function, providing a promising approach for tumor therapy. Herein, we employed polyvinylpyrrolidone (PVP)-modified Cu-gallic acid (CuGA) complex nano-boosters for amplifying lysosomes-mitochondria cascaded damage, and thereby effectively inducing cuproptosis and pyroptosis of breast tumor cells to boost anti-tumor immunotherapy. The CuGA nano-boosters could hijack lysosomal iron to form a bimetallic catalyst Cu(Fe)GA in situ through ion-exchange reaction, and cause the release of Cu+/2+ and metal ion dysregulation (i.e., Fe2+/3+, Cu+/2+, Ca2+) in tumor cells. The released Cu+ further led to metabolic disturbances of mitochondrial tricarboxylic acid (TCA) cycle (i.e., cuproptosis), and ultimately led to caspase-3/GSDME-dependent pyroptosis. In vivo results revealed that this lysosomal-mitochondrial cascade damage strategy not only induced tumor cell death, but also activated the immune response, thereby effectively suppressed tumor metastasis. This research provides a novel approach of triggering cascade damage to subcellular organelles for boosting tumor immunotherapy by disrupting metal ion intracellular homeostasis.