A Selective Nano Cell Cycle Checkpoint Inhibitor Overcomes Leukemia Chemoresistance.

Cell cycle checkpoint activation promotes DNA damage repair, which is highly associated with the chemoresistance of various cancers including acute myeloid leukemia (AML). Selective cell cycle checkpoint inhibitors are strongly demanded to overcome chemoresistance, but remain unexplored. A selective nano cell cycle checkpoint inhibitor (NCCI: citric acid capped ultra-small iron oxide nanoparticles) that can catalytically inhibit the cell cycle checkpoint of AML to boost the chemotherapeutic efficacy of genotoxic agents is now reported. NCCI can selectively accumulate in AML cells and convert H2 O2 to • OH to cleave heat shock protein 90, leading to the degradation of ataxia telangiectasia and Rad3-related proteinand checkpoint kinase 1, and the subsequent dysfunction of the G2/M checkpoint. Consequently, NCCI revitalizes the anti-AML efficacy of cytarabine that is previously ineffective both in vitro and in vivo. This study offers new insights into designing selective cell cycle checkpoint inhibitors for biomedical applications.

A self-amplified ferroptosis nanoagent that inhibits the tumor upstream glutathione synthesis to reverse cancer chemoresistance.

Ferroptosis has recently become an attractive strategy to combat the chemoresistance of cancer cells, but the intracellular ferroptosis defense system greatly challenges the efficient ferroptosis induction. Herein, we report a ferrous metal-organic framework-based nanoagent (FMN) that inhibits the intracellular upstream glutathione synthesis and induces self-amplified ferroptosis of cancer cells, for reversing chemoresistance and boosting chemotherapy. The FMN is loaded with SLC7A11 siRNA (siSLC7A11) and chemotherapeutic doxorubicin (DOX), which shows enhanced tumor cell uptake and retention, thus ensuring the effective DOX delivery and tumor intracellular iron accumulation. Importantly, the FMN simultaneously catalyzes the iron-dependent Fenton reaction and triggers the siSLC7A11-mediated suppression of upstream glutathione synthesis for intracellularly self-amplified ferroptosis, which further inhibits P-glycoprotein activity for DOX retention, and regulates the expression of Bcl-2/Bax to reverse the apoptotic resistance state of tumor cells. The FMN-mediated ferroptosis is also demonstrated in ex vivo patient-derived tumor fragment platform. Consequently, FMN successfully reverses cancer chemoresistance and achieves a highly efficient in vivo therapeutic efficacy in MCF7/ADR tumor-bearing mice. Our study provides a self-amplified ferroptosis strategy via inhibiting intracellular upstream glutathione synthesis, which is effective to reverse cancer chemoresistance.

Ultrasmall Ruthenium Nanoparticles with Boosted Antioxidant Activity Upregulate Regulatory T Cells for Highly Efficient Liver Injury Therapy.

Nanozymes exhibiting antioxidant activity are beneficial for the treatment of oxidative stress-associated diseases. Ruthenium nanoparticles (RuNPs) with multiple enzyme-like activities have attracted growing attention, but the relatively low antioxidant enzyme-like activities hinder their practical biomedical applications. Here, a size regulation strategy is presented to significantly boost the antioxidant enzyme-like activities of RuNPs. It is found that as the size of RuNPs decreases to ≈2.0 nm (sRuNP), the surface-oxidized Ru atoms become dominant, thus possessing an unprecedentedly boosted antioxidant activity as compared to medium-sized (≈3.9 nm) or large-sized counterparts (≈5.9 nm) that are mainly composed of surface metallic Ru atoms. Notably, based on their antioxidant enzyme-like activities and ultrasmall size, sRuNP can not only sustainably ameliorate oxidative stress but also upregulate regulatory T cells in late-stage acetaminophen (APAP)-induced liver injury (ALI). Consequently, sRuNPs perform highly efficient therapeutic efficiency on ALI mice even when treated at 6 h after APAP intoxication. This strategy is insightful for tuning the catalytic performances of nanozymes for their extensive biomedical applications.

A Sub-Nanostructural Transformable Nanozyme for Tumor Photocatalytic Therapy.

The structural change-mediated catalytic activity regulation plays a significant role in the biological functions of natural enzymes. However, there is virtually no artificial nanozyme reported that can achieve natural enzyme-like stringent spatiotemporal structure-based catalytic activity regulation. Here, we report a sub-nanostructural transformable gold@ceria (STGC-PEG) nanozyme that performs tunable catalytic activities via near-infrared (NIR) light-mediated sub-nanostructural transformation. The gold core in STGC-PEG can generate energetic hot electrons upon NIR irradiation, wherein an internal sub-nanostructural transformation is initiated by the conversion between CeO2 and electron-rich state of CeO2-x, and active oxygen vacancies generation via the hot-electron injection. Interestingly, the sub-nanostructural transformation of STGC-PEG enhances peroxidase-like activity and unprecedentedly activates plasmon-promoted oxidase-like activity, allowing highly efficient low-power NIR light (50 mW cm-2)-activated photocatalytic therapy of tumors. Our atomic-level design and fabrication provide a platform to precisely regulate the catalytic activities of nanozymes via a light-mediated sub-nanostructural transformation, approaching natural enzyme-like activity control in complex living systems.

A Phosphatase-Mimetic Nano-Stabilizer of Mast Cells for Long-Term Prevention of Allergic Disease.

Allergic diseases are pathological immune responses with significant morbidity, which are closely associated with allergic mediators as released by allergen-stimulated mast cells (MCs). Prophylactic stabilization of MCs is regarded as a practical approach to prevent allergic diseases. However, most of the existing small molecular MC stabilizers exhibit a narrow therapeutic time window, failing to provide long-term prevention of allergic diseases. Herein, ceria nanoparticle (CeNP-) based phosphatase-mimetic nano-stabilizers (PMNSs) with a long-term therapeutic time window are developed for allergic disease prevention. By virtue of the regenerable catalytic hotspots of oxygen vacancies on the surface of CeNPs, PMNSs exhibit sustainable phosphatase-mimetic activity to dephosphorylate phosphoproteins in allergen-stimulated MCs. Consequently, PMNSs constantly modulate intracellular phospho-signaling cascades of MCs to inhibit the degranulation of allergic mediators, which prevents the initiation of allergic mediator-associated pathological responses, eventually providing protection against allergic diseases with a long-term therapeutic time window.