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Iron-based nanozymes, recognized for their biocompatibility and peroxidase-like activities, hold promise as catalysts in tumor therapy. However, their concurrent catalase-like activity undermines therapeutic efficacy by converting hydrogen peroxide in tumor tissues into oxygen, thus diminishing hydroxyl radical production. Addressing this challenge, this study introduces the hemin–cysteine–Fe (HCFe) nanozyme, which exhibits exclusive peroxidase-like activity. Constructed through a supramolecular assembly approach involving Fmoc- l -cysteine, heme, and Fe²⁺ coordination, HCFe distinctly incorporates heme and [Fe–S] within its active center. Sulfur coordination to the central Fe atom of Hemin is crucial in modulating the catalytic preference of the HCFe nanozyme towards peroxidase-like activity. This unique mechanism distinguishes HCFe from other bifunctional iron-based nanozymes, enhancing its catalytic selectivity even beyond that of natural peroxidases. This selective activity allows HCFe to significantly elevate ROS production and exert cytotoxic effects, especially against cisplatin-resistant esophageal squamous cell carcinoma (ESCC) cells and their xenografts in female mice when combined with cisplatin. These findings underscore HCFe’s potential as a crucial component in multimodal cancer therapy, notably in augmenting chemotherapy efficacy. Iron-based nanozymes are promising for tumor catalytic therapy owing to their biocompatibility and peroxidase-like activity, but the concurrent catalase-like activity undermines the therapeutic efficacy. Here, the authors address this issue by developing a hemin–cysteine–Fe nanozyme, which exhibits catalytic selectivity and exclusive peroxidase-like activity.

Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy. Radiotherapy has the potential to induce immunogenic cell death (ICD), however radiation-induced immune responses are often limited. Here the authors design gadolinium-based nanoscale coordination polymers to amplify radiation-mediated oxidative stress, promoting ICD and anti-tumor immune responses.

Mitochondrial metabolism is an attractive target for cancer therapy 1 , 2 . Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC) 1 , 3 . Here we show that BTB and CNC homology1 (BACH1) 4 , a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin 5 , 6 , suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours 7 . Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors. The transcription factor BACH1, which targets mitochondrial metabolism, is expressed at high levels in several types of cancer; reducing its expression in tumours makes them more susceptible to treatment with mitochondrial inhibitors.

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO 3 -assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis. Radiofrequency ablation (RFA) is a minimally invasive tumor ablation method, however incomplete ablation and the induction of an immunosuppressive microenvironment limit its efficacy in the clinic. Here the authors design a pH-responsive lipoxidase-loaded nanoreactor, that by triggering ferroptosis and anti-tumor immunity, amplify the therapeutic benefits of RFA in preclinical models.

Sepsis-related acute lung injury (ALI) remains a major cause of mortality in critically ill patients and lacks specific therapy. Mitochondrial dysfunction is involved in the progression of septic lung injury. Mitochondrial dynamics, mitophagy, and biogenesis converge to constitute the assiduous quality control of mitochondria (MQC). Heme oxygenase-1 (HO-1) protects against sepsis-induced ALI through the modulation of mitochondrial dynamics. However, the causal relationship between HO-1 and the general processes of MQC, and their associated cellular pathways in sepsis-related ALI remain ill-defined. Herein, lipopolysaccharide (LPS)-induced ALI in Sprague-Dawley rats together with LPS-induced oxidative injury in RAW264.7 macrophages were used to investigate whether the PI3K/Akt pathway-mediated induction of HO-1 preserves MQC and alleviates septic lung injury. After pretreatment with hemin, a potent inducer of HO-1, LPS-induced cell apoptosis, enhanced mitochondrial fragmentation, and mitochondrial membrane potential damage were significantly reduced in macrophages. In rats, these effects were accompanied by a higher survival rate, less damage to lung tissue, a 28.5% elevation in lung mitochondria MnSOD activity, and a 39.2% increase in respiratory control ratios. Concomitantly, HO-1 induction preserved the dynamic process of mitochondrial fusion/fission (Mfn2, OPA1, Drp1), promoted mitochondrial biogenesis (NRF1, PGC1α, Tfam), and facilitated the key mediators of mitochondrial mitophagy (Parkin, PINK1) at mRNA and protein levels. Notably, LY294002, a PI3K inhibitor, or knockdown of PI3K by small interfering RNA significantly suppressed Akt phosphorylation, attenuated HO-1 induction, and further reversed these beneficial effects evoked by hemin pretreatment in RAW264.7 cells or rats received LPS, indicating a direct involvement of PI3K/Akt pathway. Taken together, our results indicated that HO-1 activation, through PI3K/Akt pathway, plays a critical role in protecting lung from oxidative injury in the setting of sepsis by regulating MQC. HO-1 may therefore be a therapeutic target for the prevention sepsis-related lung injury.

G-quadruplex/hemin DNAzymes are promising nucleic acid catalysts due to their versatility and ease of use in biosensing applications. Their peroxidase-like catalytic activity can be enhanced through various strategies, including modifications to flanking nucleotides. In this study, the catalytic effects of flanking nucleotide modifications at the 3′ and 5′ ends of the DNAzyme were investigated. Additionally, the structural topology of the G-quadruplex/hemin DNAzymes was characterized using circular dichroism (CD) spectroscopy. Similar to the unmodified DNAzyme, the modified G-quadruplex with adenine (A) nucleotide at the 3′-terminal extension adopted a parallel topology in the presence of hemin. After optimizing the reaction conditions, the kinetic parameters of both original and 3′ flanking A modified G-quadruplex/hemin DNAzymes were evaluated using the oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) in the presence of hydrogen peroxide (H 2 O 2 ). The kinetic analysis revealed a significant enhancement in catalytic efficiency upon the addition of A nucleotides at the 3′ end. Notably, the DNAzyme with a 3′-terminal AA modification exhibited approximately a ten-fold increase in catalytic efficiency compared to the unmodified form, as indicated by higher turnover numbers ( k cat ) and lower H 2 O 2 substrate affinity ( K m ). This enhanced catalytic performance was further demonstrated by improved colorimetric signal detection of circulating tumor DNA (ctDNA), underscoring the potential of the modified DNAzymes for more sensitive detection in colorimetric biosensor applications.

The emerging concept of PANoptosis—a lytic cell death pathway integrating apoptosis, pyroptosis, and necroptosis—presents avenues for cancer immunotherapy, yet its therapeutic exploitation remains limited by undefined molecular sensors and induction strategies. Here, we report a tumor-targeting nanozyme, Hemin-His-Mn, that concurrently activates retinoic acid-inducible gene I–mediated PANoptosome assembly and catalyzes reactive oxygen species amplification to achieve precision PANoptosis induction. Mechanistically, Hemin-His-Mn binds to retinoic acid-inducible gene I and alleviates its autoinhibition, initiating PANoptosome formation through the orchestrated recruitment of cell death executioners, thereby identifying retinoic acid-inducible gene I as a master PANoptosis sensor. In parallel, Hemin-His-Mn exerts peroxidase-like activity to generate cytotoxic reactive oxygen species surges, facilitating complete execution of PANoptosis. This dual mechanism promotes potent immunogenicity by releasing damage-associated molecular patterns and enhancing antigen presentation, ultimately eliciting robust T cell–mediated antitumor immunity. In multiple male mouse preclinical models, Hemin-His-Mn reprograms the tumor immune microenvironment and synergizes with immune checkpoint inhibitors. Our study introduces a retinoic acid-inducible gene I–targeting nanotechnology platform that redefines strategies for PANoptosis induction, provides mechanistic insights into PANoptosome assembly, and offers a clinically translatable modality for enhancing cancer immunotherapy. PANoptosis, a lytic cell death pathway, is promising for cancer immunotherapy, yet its therapeutic exploitation is underdeveloped. Here, the authors report a tumor-targeting nanozyme, Hemin-His-Mn, that concurrently activates retinoic acid-inducible gene I (RIG-I)–mediated PANoptosome assembly and catalyzes reactive oxygen species amplification to achieve PANoptosis induction.

Atrazine (ATZ) is used extensively, resulting in residues in food and the environment, posing a serious threat to human health. Herein, Cd 0.5 Zn 0.5 S/Ti 3 C 2 photoelectric material was synthesized and immobilized on a FTO electrode as a photoanode. A photoelectrochemical (PEC) aptamer sensor was constructed for the highly sensitive and selective determination of ATZ based on signal amplification via cascade catalysis of CRISPR/Cas12a and G-quadruplex/hemin DNAzyme (G4/hemin DNAzyme). G4/hemin DNAzyme catalyses the oxidation reaction between H 2 O 2 and dopamine (DA) to form polydopamine (PDA) deposit. This process, in turn, inhibits the photocurrent at the photoanode, leading to a decrease in photocurrent. Concurrently, the depletion of DA as an electron donor for the PEC reaction at the photoelectrode further contributes to the decrease in photocurrent. ATZ can hybridize with ATZ aptamer (Apt) in Apt/cDNA to release activation strand (cDNA), which activates the activity of CRISPR/Cas12a and triggers cleavage of G4, causing the cleaving of G4/hemin DNAzyme immobilized on the electrode surface. This process leads to a decrease of G4/hemin DNAzymes amount on the electrode, consequently reducing both the PDA generation and the DA consumption. As a result, the photocurrent is restored. The cascade catalysis of CRISPR/Cas12a and G4/hemin DNAzyme has been demonstrated to result in photocurrent amplification. The photocurrent change was linear with the logarithmic value of ATZ concentration in the range 1.00 × 10 –12 to 1.00 × 10 –5  mol/L. The limit of detection was 3.47 × 10 –13  mol/L. The sensor has been successfully applied to the determination of trace ATZ in environmental and food samples. Graphical abstract

The development of sensitive and specific methods for the high-quality analysis of hemin-related drugs is significant in the pharmaceutical field. In this work, a simple and rapid method based on the fluorescent properties of carbon dots (CDs) was established for the determination of hemin in drugs. By taking melamine and ethylenediamine as the reaction materials, the fluorescent CDs were synthesized by a one-step solvothermal method, which can be used for the determination of hemin in drugs by the fluorescent inner filter effect. The as-prepared fluorescent CDs with rich functional groups on the surface displayed good water solubility, strong salt resistance, robust pH stability, and photobleaching resistance. Most importantly, the fluorescent excitation wavelength of fluorescent CDs was very close to the absorption wavelength of hemin, providing the evidence for the fluorescent inner filter effect. When the hemin concentration was in the range of 0.01–1 μM, there was a good linear relationship between the hemin content with the fluorescence intensity of CDs. The linear regression equation was (1 − F/F0) = 0.0897c + 0.0124, with a correlation coefficient (R2) of 0.9982 and a detection limit of 9 nM. This assay was successfully used to determine the content of hemin in the tablet, which displayed 97.9–105.5% of the labelled amount, with a relative standard deviation of less than 3%. The developed fluorescence method for the detection of hemin content displays the advantages of accurate, rapid, and high sensitivity, which could prove to be a useful tool for the determination of hemin supplement tablets.

Heme (iron-protoporphyrin IX) is an essential but potentially toxic cellular cofactor. While most organisms are heme prototrophs, many microorganisms can utilize environmental heme as iron source. The pathogenic yeast Candida albicans can utilize host heme in the iron-poor host environment, using an extracellular cascade of soluble and anchored hemophores, and plasma membrane ferric reductase-like proteins. To gain additional insight into the C . albicans heme uptake pathway, we performed an unbiased genetic selection for mutants resistant to the toxic heme analog Ga 3+ -protoporphyrin IX at neutral pH, and a secondary screen for inability to utilize heme as iron source. Among the mutants isolated were the genes of the pH-responsive RIM pathway, and a zinc finger transcription factor related to S . cerevisiae HAP1 . In the presence of hemin in the medium, C . albicans HAP1 is induced, the Hap1 protein is stabilized and Hap1-GFP localizes to the nucleus. In the hap1 mutant, cytoplasmic heme levels are elevated, while influx of extracellular heme is lower. Gene expression analysis indicated that in the presence of extracellular hemin, Hap1 activates the heme oxygenase HMX1 , which breaks down excess cytoplasmic heme, while at the same time it also activates all the known heme uptake genes. These results indicate that Hap1 is a heme-responsive transcription factor that plays a role both in cytoplasmic heme homeostasis and in utilization of extracellular heme. The induction of heme uptake genes by C . albicans Hap1 under iron satiety indicates that preferential utilization of host heme can be a dietary strategy in a heme prototroph.