Ziyi Li

Introduction: Photothermal therapy (PTT) faces limitations due to tumor microenvironment (TME) heterogeneity and single-modality constraints, including hypoxia, redox imbalance, and uneven heat distribution, which compromise therapeutic durability. Integrating nanozyme catalysis with PTT presents a promising strategy to amplify oxidative stress, yet achieving a balance among catalytic efficiency, photothermal performance, biocompatibility, and stability remains challenging. Methods: Herein, we developed an epigallocatechin gallate (EGCG)-modified palladium-based nanozyme (EGCG-PdZyme) for the precision treatment of esophageal cancer. This multifunctional platform was engineered to integrate catalase-like oxygen generation, peroxidase-like reactive oxygen species (ROS) production, and near-infrared photothermal conversion capabilities. Results: While EGCG modification slightly attenuated the intrinsic catalytic activity and peak photothermal temperature, it established an optimized thermo-catalytic synergy. Sustained mild hyperthermia amplified oxidative stress, effectively offsetting the reduced catalytic output and minimizing thermal damage to peritumoral tissues. Mechanistically, persistent photothermal heating boosted enzymatic ROS generation within the TME, initiating a self-amplifying therapeutic cascade. Furthermore, EGCG functionalization significantly enhanced colloidal stability and biosafety, enabling effective tumor ablation with negligible systemic toxicity. Discussion: This study demonstrates a paradigm shift from maximizing isolated parameters toward achieving a dynamic equilibrium between catalytic functionality and biological compatibility. By integrating TME modulation with controlled photothermal amplification, the EGCG-PdZyme platform offers a viable strategy for clinically translatable precision oncotherapy.

The online version contains supplementary material available at 10.1038/s41598-026-49669-8.

Globally, esophageal cancer (EC) is the seventh most commonly diagnosed cancer and the sixth leading cause of cancer-related death. However, its treatment remains challenging due to significant obstacles. Photothermal therapy (PTT), a minimally invasive technique, has emerged as a promising method for tumor ablation. However, its efficacy is limited by low photothermal conversion efficiency and poor tissue penetration. To address these limitations, this study developed a metal-organic framework (MOF)-based nanozyme for the treatment of EC. In this system, the dye IR780, used for photothermal conversion, was encapsulated in liposomes and anchored onto the MOF nanozyme, resulting in a Pt@MOF@PSs construct that improved the aqueous stability of IR780. This multifunctional nanozyme showed tumor-targeting and synergistic therapeutic effects. After passive accumulation in EC tissues, Pt@MOF@PSs suppressed hypoxia and promoted reactive oxygen species (ROS) production by using the high H ₂ O ₂ levels typical of the tumor microenvironment. The PTT activity of Pt@MOF@PSs was confirmed by its significant temperature increase and upregulation of heat shock protein 70 after irradiation with an 808 nm near-infrared laser. These features facilitated the effective modulation of the resistant tumor microenvironment, induced localized hyperthermia, exerted potent cytotoxicity against esophageal squamous carcinoma cells (ESCs), and suppressed EB tumor progression. These findings highlight Pt@MOF@PSs as a promising therapeutic option, integrating hypoxia relief, ROS generation, and PTT for improved therapeutics against EC.

Existing immunodeficient pig models have demonstrated limited success in supporting robust human haematopoietic engraftment and multilineage differentiation. Here we hypothesize that the targeted deletion of integrin-associated protein (Cd47) in severe combined immunodeficient pigs, with deletions in the X-linked interleukin-2 receptor gamma chain and recombination activating gene 1, would enable long-term haematopoietic engraftment following transplantation with human haematopoietic stem/progenitor cells. In Cd47-deficient pigs, we observed high levels of human haematopoietic chimerism in the blood and spleen, with functional T and B lymphocytes, natural killer and myeloid cells, as well as robust thymopoiesis. Our findings suggest that severe combined immunodeficient pigs with Cd47 deletion represent an improved preclinical model for studying human haematopoiesis, disease mechanisms and therapies, and offer potential as a bioreactor for large-scale production of human immune cells.

As the first acetylated nucleoside to be discovered, N‐acetyltransferase 10 (NAT10)‐catalyzed RNA N4‐acetylcytidine (ac ⁴ C) modification is involved in the occurrence of various diseases. However, the roles of RNA ac ⁴ C in preimplantation embryo development still need more detailed studies. Here, we analyzed the role of RNA ac ⁴ C in preimplanted embryonic development in mice through Nat10 siRNA microinjection and growing oocyte stage‐specific Nat10 knockout (Zp3‐ Nat10 ^lox/lox ). We found that NAT10 was indispensable for both the morula‐to‐blastocyst transition and zygotic genome activation (ZGA). Nat10 knockdown by Nat10 siRNA microinjection caused most embryos to arrest at the morula stage, and the expression levels of NANOG and CDX2 were significantly decreased. Moreover, the mRNA stability of Nanog was also significantly decreased in morulae after Nat10 knockdown. Zp3‐ Nat10 ^lox/lox female mice were completely sterile, and the embryos from Zp3‐ Nat10 ^lox/lox females were arrested at the 2‐cell stage. Both the degradation of maternal mRNA and ZGA were deficient in 2‐cell embryos from Zp3‐ Nat10 ^lox/lox females. In conclusion, our findings demonstrate that NAT10 is crucial for both ZGA and the morula‐to‐blastocyst transition processes during mouse preimplantation embryonic development.

The Myc family is essential for cell proliferation, differentiation, and metabolism, particularly in embryonic development and stem cell functions. However, the specific role of Myc in porcine early embryonic development is not fully understood. This study observed high Myc expression during the four-cell stage of porcine embryos. Inhibition of Myc using 10058-F4 impaired embryonic development, disrupted energy metabolism, and increased DNA methylation. Mechanistically, these effects were dependent on α-KG, a TCA cycle intermediate and cofactor for TET demethylation enzymes. Sequencing analysis of four-cell embryos post-Myc inhibition revealed downregulation of key metabolic enzymes related to α-KG, such as CS, IDH2, leading to reduced α-KG levels. Supplementation with α-Ketoglutarate (α-KG) mitigated the negative effects of Myc inhibition, including lower blastocyst rates, decreased ATP levels, and increased 5 mC levels. In conclusion, Myc regulates the expression of key metabolic enzymes during the four-cell stage, influencing early embryonic metabolism and epigenetic reprogramming.

: In brief: During zygotic genome activation, thousands of genes are activated, and those pre-mRNAs must be accurately spliced to support the production of functional proteins. This study shows that SON is necessary for proper nuclear speckle organization, pre-mRNA splicing, transcriptome establishment, and histone methylation in mouse preimplantation embryos. Thousands of genes are activated in late two-cell embryos, which means that numerous pre-mRNAs are generated during this time. These pre-mRNAs must be accurately spliced to ensure that the mature mRNAs are translated into functional proteins. However, little is known about the roles of pre-mRNA splicing and the cellular factors modulating pre-mRNA splicing during early embryonic development. Here, we report that downregulation of SON, a large Ser/Arg (SR)-related protein, reduced embryonic development and caused deficient blastomere cleavage. These embryonic developmental defects result from dysregulated nuclear speckle organization and pre-mRNA splicing of a set of cell cycle-related genes. Furthermore, SON downregulation disrupted the transcriptome (2128 upregulated and 1399 downregulated) in four-cell embryos. Increased H3K4me3, H3K9me3, and H3K27me3 levels were detected in four-cell embryos after SON downregulation. Taken together, these results demonstrate that accurate pre-mRNA splicing is essential for early embryonic development and that SON plays important roles in nuclear speckle organization, pre-mRNA splicing, transcriptome establishment, and histone methylation reprogramming during early embryonic development.

To obtain high-quality bovine oocytes, the effects of vitamin C (VC) on the IVM of bovine oocytes and early embryo development were investigated. The results showed the following. (1) The IVM medium containing 50 µg/mL VC improved the oocyte maturation rate but did not affect the parthenogenetic embryo development. (2) The IVC medium containing 20 µg/mL VC improved the cleavage rate of the IVF embryos and enhanced the mRNA transcriptions of pluripotency gene Oct4, Sox2, Cdx2, and Nanog in the blastocysts but had no effects on the blastocyst rate. (3) Combining supplementation of 50 µg/mL VC in IVM medium + 20 µg/mL VC in IVC medium (named as VC 50/20, similar hereinafter) elevated the cleavage rate of IVF embryos and enhanced the mRNA expressions of Oct4, Sox2, Cdx2, and Nanog in the blastocysts. (4) Combination of VC 0/20 and VC 50/20 enhanced the transcription of anti-apoptotic gene Bcl-2 and VC 50/0 weakened the transcription of pro-apoptotic gene Bax, while VC 0/40 and VC 0/60 increased Bax expression and diminished the Bcl-2/Bax ratio in blastocysts. Together, employing 50 µg/mL VC improves the IVM of bovine oocytes and combination of VC 50/20 potentially changes bovine embryo quality by enhancing the expressions of the pluripotency genes and regulating the expressions of apoptosis-related genes.