A Bimetallic Metal-Organic-Framework-Based Biomimetic Nanoplatform Enhances Anti-Leukemia Immunity via Synchronizing DNA Demethylation and RNA Hypermethylation.

Epigenetic-alterations-mediated antigenicity reducing in leukemic blasts (LBs) is one of the critical mechanisms of immune escape and resistance to T-cell-based immunotherapy. Herein, a bimetallic metal-organic framework (MOF)-based biomimetic nanoplatform (termed as AFMMB) that consists of a DNA hypomethylating agent, a leukemia stem cell (LSC) membrane, and pro-autophagic peptide is fabricated. These AFMMB particles selectively target not only LBs but also LSCs due to the homing effect and immune compatibility of the LSC membrane, and induce autophagy by binding to the Golgi-apparatus-associated protein. The autophagy-triggered dissolution of AFMMB releases active components, resulting in the restoration of the stimulator of interferon genes pathway by inhibiting DNA methylation, upregulation of major histocompatibility complex class-I molecules, and induction of RNA-methylation-mediated decay of programmed cell death protein ligand transcripts. These dual epigenetic changes eventually enhance T-cell-mediated immune response due to increased antigenicity of leukemic cells. AFMMB also can suppress growth and metastases of solid tumor, which was suggestive of a pan-cancer effect. These findings demonstrate that AFMMB may serve as a promising new nanoplatform for dual epigenetic therapy against cancer and warrants clinical validation.

Glycyrrhetinic acid nanoparticles combined with ferrotherapy for improved cancer immunotherapy.

Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) blockade immunotherapy has emerged as a promising strategy to treat both solid and hematological malignancies. Despite the considerable therapeutic effects obtained in pre-clinical and clinical studies, PD-1/PD-L1 blockade therapy is still limited by the low benefit rates and a large number of patients still do not respond to this treatment. In this study, we developed a highly efficient and cancer-specific immunogenic cell death nanoinducer for effective tumor immunotherapy. A leukocyte membrane coated poly (lactic-co-glycolic acid) encapsulating glycyrrhetinic acid (GCMNPs) was developed to enhance targeting, tumor-homing capacity, and reduce toxicity in vivo. GCMNPs could induce ferroptosis in acute myeloid leukemia and colorectal cancer cells by downregulating glutathione-dependent peroxidases 4, leading to increased lipid peroxidation levels. Moreover, GCMNPs and ferumoxytol could synergistically enhance Fe-dependent cytotoxicity through the Fenton reaction. Finally, in vivo studies showed that GCMNPs synergized with ferumoxytol and anti-PD-L1 synergistically improve T-cell immune response against leukemia and colorectal tumor. This study anticipated that the combination of glycyrrhetinic acid-based nanomaterials and ferrotherapy would provide further insights into anti-cancer immune response to PD-1/PD-L1 blockade for both solid and hematological malignancies. STATEMENT OF SIGNIFICANCE: Despite the considerable therapeutic effects obtained in pre-clinical and clinical studies, PD-1/PD-L1 blockade therapy is still limited by the low benefit rates and a large number of patients still do not respond to this treatment. We designed a glycyrrhetinic acid-based nanoplatform as a new ICD inducer (GCMNPs), with high cancer cell specificity and reduced toxicity to AML and CRC. GCMNPs cooperates with ferumoxytol to promote a Fenton reaction and induce ferroptosis. Moreover, the combination of GCMNPs and ferumoxytol enhanced the blockage of PD-1/PD-L1 to activate T cells, subsequently generating a systemic immune response in CRC and AML mouse models. This pre-clinical findings provide the proof-of-concept of combination of glycyrrhetinic acid-based nanomaterials and ferrotherapy as an "ICD nano-inducer" and immunotherapeutic agent for treating cancer.

Glutathione-Bioimprinted Nanoparticles Targeting of N6-methyladenosine FTO Demethylase as a Strategy against Leukemic Stem Cells.

The N6-methyladenosine (m6 A) demethylase FTO plays an oncogenic role in acute myeloid leukemia (AML). Despite the promising recent progress for developing some small-molecule FTO inhibitors, the clinical potential remains limited due to mild biological function, toxic side effects and low sensitivity and/or specificity to leukemic stem cells (LSCs). Herein, FTO inhibitor-loaded GSH-bioimprinted nanocomposites (GNPIPP12MA) are developed that achieves targeting of the FTO/m6 A pathway synergized GSH depletion for enhancing anti-leukemogenesis. GNPIPP12MA can selectively target leukemia blasts, especially LSCs, and induce ferroptosis by disrupting intracellular redox status. In addition, GNPIPP12MA increases global m6 A RNA modification and decreases the transcript levels in LSCs. GNPIPP12MA augments the efficacy of the PD-L1 blockade by increasing the infiltration of cytotoxic T cells for enhanced anti-leukemia immunity. This study offers insights for a GSH-bioimprinted nanoplatform targeting m6 A RNA methylation as a synergistic treatment strategy against cancer stem cells that may translate to clinical applications.

Gold Nanorods Exhibit Intrinsic Therapeutic Activity via Controlling N6-Methyladenosine-Based Epitranscriptomics in Acute Myeloid Leukemia.

Reprograming the N6-methyladenosine (m6A) landscape is a promising therapeutic strategy against recalcitrant leukemia. In this study, we synthesized gold nanorods (GNRs) of different aspect ratios using a binary surfactant mixture of hexadecyltrimethylammonium bromide and sodium oleate. Following surface functionalization with chitosan and a 12-mer peptide, GNRa-CSP12 measuring 130 × 21 nm2 was selectively taken up by leukemia cells via targeted endocytosis. Low doses of GNRa-CSP12 inhibited the growth of leukemia cells by disrupting the redox balance and inducing ferroptosis. Mechanistically, GNRa-CSP12 abrogated endogenous Fe2+-dependent m6A demethylase activity, which led to global m6A hypomethylation and post-transcriptional regulation of downstream genes that are involved in glycolysis, hypoxia, and immune checkpoint pathways. In addition, combination treatment with GNRa-CSP12 and tyrosine kinases inhibitors (TKIs) synergistically obviated the m6A-mediated TKI resistance phenotype. Finally, GNRa-CSP12 as a potential immunotherapeutic agent could enhance immunotherapy outcome in leukemia. Our preclinical findings provide the proof-of-concept for targeting m6A-methylation-based epitranscriptomics using nanoparticle as an "epigenetic drug" for cancer therapy.

Photothermal therapy mediated by gold nanocages composed of anti-PDL1 and galunisertib for improved synergistic immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. The primary treatment for CRC is surgical resection, along with chemotherapy in more advanced or inoperable cases. There is a growing interest to complement both curative and palliative treatment with immunotherapies such as the programmed cell death-1 (PD-1) and PD-ligand 1 (PDL1) checkpoint inhibitors and transforming growth factor (TGF) ß inhibitors. However, the clinical outcomes of current immunotherapeutic strategies are limited by tumor heterogeneity and drug resistance. Nanomedicine-based photothermal therapy (PTT) has shown encouraging results for solid tumor ablation. Herein, we designed and synthesized gold nanocages functionalized with primary macrophage membrane and surface anti-PDL1 antibody, and loaded with a TGFß inhibitor, galunisertib. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC. STATEMENT OF SIGNIFICANCE: The combination of photothermal therapy (PTT) with immunotherapy can achieve an inherently synergistic anti-tumor effect. Here we integrated low-temperature PTT, PDL1 antibody and TGF-ß inhibitor in hollow gold nanocage nanocomposites (GNC-Gal@CMaP) that selectively targeted colon cancer cells and accumulated in the tumor microenvironment. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC.

Ataxia telangiectasia mutated inhibitor-loaded copper sulfide nanoparticles for low-temperature photothermal therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is ranked the sixth most common neoplasm and the third leading cause of cancer-related deaths. Photothermal therapy (PTT) for thermal ablation of local tumors has recently emerged as a therapeutic strategy. However, the relatively high temperature of over 50 °C may lead to unexpected heat-related damage to tumor-adjacent normal tissues. Herein, we designed and synthesized ataxia telangiectasia mutated (ATM) inhibitor loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs are highly photo-stable, can release encapsulated drugs, and increase the temperature to an effective level in a near-infrared (NIR)-responsive manner. Moreover, CuS-ATMi@TGF-ß NPs specifically target tumors and thereby significantly inhibit tumor growth on contribution to synergistic low-temperature PTT and chemotherapy. This system not only achieved low-temperature PTT but also resulted in reduced damage to normal tissues. Modification with anti-TGF-ß antibody enhanced target specificity and immune activation. The combination of PTT and ATM inhibitor showed synergistic effects and significantly attenuated the growth of the HCC via down regulation of heat shock protein (HSP). CuS-ATMi@TGF-ß NPs are a highly promising platform for targeted tumor ablation via hyperthermia-mediated tumor death with minimal damage to normal tissues at a low temperature. STATEMENT OF SIGNIFICANCE: We constructed ataxia telangiectasia mutated (ATM) inhibitor-loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs not only achieved low-temperature photothermal therapy (PTT) but also resulted in reduced damage to normal tissues and sufficient biocompatibility. The modification with anti-TGF-ß antibody enhanced targeted specificity, cell endocytosis, and immune activation. In addition, the combination of PTT and ATM inhibitor synergistically attenuated the growth of the HCC via downregulation of heat shock protein (HSP). This study provided proof-of-concept for the ATM inhibitor that mediated low-temperature PTT with a potential for future clinical applications.

Phytotoxicity of ionic liquids with different structures on wheat seedlings and evaluation of their toxicity attenuation at the presence of modified biochar by adsorption effect.

The toxic effects of eight common ionic liquids (ILs) on wheat seedlings was evaluated with specific emphasis on the influence of concentration range, anion species and cation chain length of ILs. The growth of wheat seeds was significantly inhibited by ILs, especially under higher concentration, presence of the fluoride anion and the longer alkyl chain length of the cation. The modified biochar (PB-K-N) efficiently removed the ILs from aqueous solutions, the order of the adsorption capacities was as follows: [Bmim]OAc [Bmim]C7H5O2 [Bmim]BF4 [Bmim]Br, [Domim]Br [BPy]Br [Omim]Br [Bmim]Br [Emim]Br. Furthermore, the wheat growth of all ILs groups except [Bmim]BF4 group in the presence of PB-K-N was also similar to that of the control groups, which clearly demonstrated that PB-K-N could decrease or alleviate toxicity of ILs toward wheat by adsorption effect. Therefore, the biochar application was effective in improving plant resistance to ILs stress by adsorption, to reduce the phytotoxicity of ILs and provide an alternative approach for the utilization of PB-K-N in ILs contaminated water and soils.