Dynamically Stabilized Electronic Regulation and Electrochemical Reconstruction in Co and S Atomic Pair Doped Fe3 O4 for Water Oxidation.

The electronic regulation and surface reconstruction of earth-abundant electrocatalysts are essential to efficient oxygen evolution reaction (OER). Here, an inverse-spinel Co,S atomic pair codoped Fe3 O4 grown on iron foam (Co,S-Fe3 O4 /IF) is fabricated as a cost-effective electrocatalyst for OER. This strategy of Co and S atomic pair directional codoping features accelerates surface reconstruction and dynamically stabilizes electronic regulation. CoS atomic pairs doped in the Fe3 O4 crystal favor controllable surface reconstruction via sulfur leaching, forming oxygen vacancies and Co doping on the surface of reconstructed FeOOH (Co-FeOOH-Ov /IF). Before and after surface reconstruction via in situ electrochemical process, the Fe sites with octahedral field dynamically maintains an appropriate electronic structure for OER intermediates, thus exhibiting consistently excellent OER performance. The electrochemically tuned Fe-based electrodes exhibit a low overpotential of 349 mV at a current density of 1000 mA cm-2 , a slight Tafel slope of 43.3 mV dec-1 , and exceptional long-term electrolysis stability of 200 h in an alkaline medium. Density functional theory calculations illustrate the electronic regulation of Fe sites, changes in Gibbs free energies, and the breaking of the restrictive scaling relation between OER intermediates. This work provides a promising directional codoping strategy for developing precatalysts for large-scale water-splitting systems.

Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer.

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential of targeting undruggable pathogenic proteins. After the first proof-of-concept proteolysis-targeting chimeric (PROTAC) molecule was reported, the TPD field has entered a new era. In addition to PROTAC, numerous novel TPD strategies have emerged to expand the degradation landscape. However, their physicochemical properties and uncontrolled off-target side effects have limited their therapeutic efficacy, raising concerns regarding TPD delivery system. The combination of TPD and nanotechnology offers great promise in improving safety and therapeutic efficacy. This review provides an overview of novel TPD technologies, discusses their clinical applications, and highlights the trends and perspectives in TPD nanomedicine.

High-Throughput CRISPR/Cas9 Mutagenesis Streamlines Trait Gene Identification in Maize.

Maize (Zea mays) is one of the most important crops in the world. However, few agronomically important maize genes have been cloned and used for trait improvement, due to its complex genome and genetic architecture. Here, we integrated multiplexed CRISPR/Cas9-based high-throughput targeted mutagenesis with genetic mapping and genomic approaches to successfully target 743 candidate genes corresponding to traits relevant for agronomy and nutrition. After low-cost barcode-based deep sequencing, 412 edited sequences covering 118 genes were precisely identified from individuals showing clear phenotypic changes. The profiles of the associated gene-editing events were similar to those identified in human cell lines and consequently are predictable using an existing algorithm originally designed for human studies. We observed unexpected but frequent homology-directed repair through endogenous templates that was likely caused by spatial contact between distinct chromosomes. Based on the characterization and interpretation of gene function from several examples, we demonstrate that the integration of forward and reverse genetics via a targeted mutagenesis library promises rapid validation of important agronomic genes for crops with complex genomes. Beyond specific findings, this study also guides further optimization of high-throughput CRISPR experiments in plants.

Ligand Modulation of Active Sites to Promote Cobalt-Doped 1T-MoS2 Electrocatalytic Hydrogen Evolution in Alkaline Media.

Highly efficient hydrogen evolution reaction (HER) electrocatalyst will determine the mass distributions of hydrogen-powered clean technologies, while still faces grand challenges. In this work, a synergistic ligand modulation plus Co doping strategy is applied to 1T-MoS2 catalyst via CoMo-metal-organic frameworks precursors, boosting the HER catalytic activity and durability of 1T-MoS2 . Confirmed by Cs corrected transmission electron microscope and X-ray absorption spectroscopy, the polydentate 1,2-bis(4-pyridyl)ethane ligand can stably link with two-dimensional 1T-MoS2 layers through cobalt sites to expand interlayer spacing of MoS2 (Co-1T-MoS2 -bpe), which promotes active site exposure, accelerates water dissociation, and optimizes the adsorption and desorption of H in alkaline HER processes. Theoretical calculations indicate the promotions in the electronic structure of 1T-MoS2 originate in the formation of three-dimensional metal-organic constructs by linking π-conjugated ligand, which weakens the hybridization between Mo-3d and S-2p orbitals, and in turn makes S-2p orbital more suitable for hybridization with H-1s orbital. Therefore, Co-1T-MoS2 -bpe exhibits excellent stability and exceedingly low overpotential for alkaline HER (118 mV at 10 mA cm-2 ). In addition, integrated into an anion-exchange membrane water electrolyzer, Co-1T-MoS2 -bpe is much superior to the Pt/C catalyst at the large current densities. This study provides a feasible ligand modulation strategy for designs of two-dimensional catalysts.

In situ Engineering of Tumor-Associated Macrophages via a Nanodrug-Delivering-Drug (ß-Elemene@Stanene) Strategy for Enhanced Cancer Chemo-Immunotherapy.

Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno-oncology. Here, we report an innovative nanodrug-delivering-drug (STNSP@ELE) strategy that leverages two-dimensional (2D) stanene-based nanosheets (STNSP) and ß-Elemene (ELE), a small-molecule anticancer drug, to overcome TAM-mediated immunosuppression and improve chemo-immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor-supportive M2-like TAMs into a tumor-suppressive M1-like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2-like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo-immunotherapeutic nanoplatform has immune-modulatory capabilities that can overcome TAM-mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug-delivering-drug strategy in developing other nano-immunotherapeutics and treating various types of immunosuppressive tumors.

A nano-innate immune system activator for cancer therapy in a 4T1 tumor-bearing mouse model.

BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy.

Crop genome-wide association study: a harvest of biological relevance.

With the advent of rapid genotyping and next-generation sequencing technologies, genome-wide association study (GWAS) has become a routine strategy for decoding genotype-phenotype associations in many species. More than 1000 such studies over the last decade have revealed substantial genotype-phenotype associations in crops and provided unparalleled opportunities to probe functional genomics. Beyond the many 'hits' obtained, this review summarizes recent efforts to increase our understanding of the genetic architecture of complex traits by focusing on non-main effects including epistasis, pleiotropy, and phenotypic plasticity. We also discuss how these achievements and the remaining gaps in our knowledge will guide future studies. Synthetic association is highlighted as leading to false causality, which is prevalent but largely underestimated. Furthermore, validation evidence is appealing for future GWAS, especially in the context of emerging genome-editing technologies.

Enhanced Photothermal Therapy through the In Situ Activation of a Temperature and Redox Dual-Sensitive Nanoreservoir of Triptolide.

Photothermal therapy (PTT) has attracted tremendous attention due to its noninvasiveness and localized treatment advantages. However, heat shock proteins (HSPs) associated self-preservation mechanisms bestow cancer cells thermoresistance to protect them from the damage of PTT. To minimize the thermoresistance of cancer cells and improve the efficacy of PTT, an integrated on-demand nanoplatform composed of a photothermal conversion core (gold nanorod, GNR), a cargo of a HSPs inhibitor (triptolide, TPL), a mesoporous silica based nanoreservoir, and a photothermal and redox di-responsive polymer shell is developed. The nanoplatform can be enriched in the tumor site, and internalized into cancer cells, releasing the encapsulated TPL under the trigger of intracellular elevated glutathione and near-infrared laser irradiation. Ultimately, the liberated TPL could diminish thermoresistance of cancer cells by antagonizing the PTT induced heat shock response via multiple mechanisms to maximize the PTT effect for cancer treatment.

CRISPR-Local: a local single-guide RNA (sgRNA) design tool for non-reference plant genomes.

SUMMARY: CRISPR-Local is a high-throughput local tool for designing single-guide RNAs (sgRNAs) in plants and other organisms that factors in genetic variation and is optimized to generate genome-wide sgRNAs. CRISPR-Local outperforms other sgRNA design tools in the following respects: (i) designing sgRNAs suitable for non-reference varieties; (ii) screening for sgRNAs that are capable of simultaneously targeting multiple genes; (iii) saving computational resources by avoiding repeated calculations from multiple submissions and (iv) running offline, with both command-line and graphical user interface modes and the ability to export multiple formats for further batch analysis or visualization. We have applied CRISPR-Local to 71 public plant genomes, using both CRISPR/Cas9 and CRISPR/cpf1 systems. AVAILABILITY AND IMPLEMENTATION: CRISPR-Local can be freely downloaded from http://crispr.hzau.edu.cn/CRISPR-Local/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Enhanced Drug Delivery by Nanoscale Integration of a Nitric Oxide Donor To Induce Tumor Collagen Depletion.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

Dynamic changes in chromatin and microtubules at the first cell cycle in SCNT or IVF goat embryos.

We investigated the dynamic changes in chromatin and microtubules at the first cell cycle in goat somatic cell nuclear transfer (SCNT)-derived and in vitro fertilization (IVF)-derived embryos. Stage-dependent and characteristic changes to chromatin and microtubules occurred in SCNT-derived embryos at different times after activation. About half donor nuclei underwent premature chromosome condensation (PCC) at 1 h post activation, and furtherly reached telophase at 2 h after activation. However, we discovered that the separated chromosomes reaggregated, not keeping two independent nuclei; and formed one pronucleus at 2.5 h after activation. One pronucleus was found in all reconstructed oocytes except other no nucleus oocytes from 3 to 22 h after activation. Reconstructed oocytes reached the first mitotic metaphase at 23 h post activation, which was later than that of IVF-derived embryos at 16 h after insemination. SCNT-derived embryos showed significantly higher abnormalities in the first mitotic metaphase spindle, compared with IVF-derived embryos. Abnormal spindles included multi polar and half spindles. SCNT-derived embryos began to cleave at 24 h after activation, which was later than that of IVF-derived embryos at 21 h after insemination. SCNT-derived embryos showed delayed conversion from telophase to interphase than IVF-derived embryos during cleavage. These might lead to poor development in SCNT-derived embryos.

IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance.

Multidrug resistance is the main cause of clinical chemotherapeutic failure. Antiangiogenic cancer therapy with nanomedicine that allows the targeted delivery of antiangiogenic agents to tumor endothelial cells may contribute to innovative strategies for treating multidrug-resistant cancers. In this study, we developed a new nanodrug delivery system (nano-DDS), with improved antiangiogenic efficacy against multidrug resistant human breast cancer MCF-7/ADR cells. Here, the IF7 ligand was a peptide designed to bind the annexin 1 (Anxa 1), a highly specific marker of the tumor vasculature surface, with high affinity and specificity. IF7-conjugated Anxa 1-targeting nanoparticles containing paclitaxel (IF7-PTX-NP) allowed controlled drug release and displayed favorable prolonged circulation in vivo. IF7-PTX-NP was significantly internalized by human umbilical vein endothelial cells (HUVEC) through the IF7-Anxa 1 interaction, and this facilitated uptake enhanced the expected antiangiogenic activity of inhibiting HUVEC proliferation, migration, and tube formation in a Matrigel plug relative to those of Taxol and PTX-NP. As IF7-PTX-NP targeted the tumor vessels, more nanoparticles accumulated in MCF-7/ADR tumors, and more importantly, induced significant apoptosis of the tumor vascular endothelial cells and necrosis of the tumor tissues. Low dose paclitaxel (1 mg/kg) formulated in IF7-PTX-NP showed significant anticancer efficacy, delaying the growth of MCF-7/ADR tumors. The same efficacy was only obtained with an 8-fold dose of paclitaxel (8 mg/kg) as Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of IF7-PTX-NP was strongly associated with the improved antiangiogenic effect, evident as a dramatic reduction in the tumor microvessel density and pronounced increase in apoptotic tumor cells, with no obvious toxicity to the mice. This nano-DDS, which targets the tumor neovasculature, offers a promising strategy for the treatment of multidrug-resistant cancer.

Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway.

Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases.

Bimetallic metal-organic framework-derived bamboo-like N-doped carbon nanotube-encapsulated Ni-doped MoC nanoparticles for water oxidation.

Molybdenum carbide materials with unique electronic structures have received special attention as water-splitting catalysts, but their structural stability in the alkaline water electrolysis process is not satisfactory. This study reports an in situ pyrolysis method for preparing NiMo-based metal-organic framework (MOF)-derived chain-mail oxygen evolution reaction (OER) electrocatalysts and bamboo-like N-doped carbon nanotube (NCNT)-encapsulated Ni-doped MoC nanoparticles (NiMoC-NCNTs). The NCNTs can provide chain mail shells to protect the inner highly reactive Ni-doped MoC cores from electrochemical corrosion by the alkaline electrolyte and regulate their catalytic properties through charge redistribution. Benefiting from high N-doping with abundant pyridinic moieties and abundant active sites of the periodic bamboo-like nodes, the as-prepared NiMoC-NCNTs display an outstanding activity for the OER with an overpotential of 310 mV at 10 mA cm-2 and a superior long-term stability of 50 h. Density functional theory calculations reveal that the excellent electrocatalytic activity of NiMoC-NCNTs comes from the electron transfer from NiMoC nanoparticles to NCNTs, resulting in a decrease in the local work function at the carbon surface and optimized free efficiencies of OER intermediates on C sites. This work provides an effective approach to improve the structural stability of fragile catalysts by equipping them with carbon-based chain.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.

Fine-tuning of xylose metabolism in genetically engineered Saccharomyces cerevisiae by scattered integration of xylose assimilation genes.

Manipulation of multiple genes is a common experience in metabolic engineering and synthetic biology studies. Chromosome integration of multiple genes in one single position is always performed, however, there is so far no study on the integration of multiple genes separately in various positions (here in after referred to as "scattered integration") and its effect on fine-tuning of cellular metabolism. In this study, scattered integration of the xylose assimilation genes PsXR, PsXDH and ScXK was investigated in Saccharomyces cerevisiae, and transcription analysis of these genes as well as their enzyme activities were compared with those observed when the genes were integrated into one single site (defined as "tandem integration" here). Not only notable differences in transcription levels and enzyme activities were observed when the genes were integrated by the two strategies, but also change of the cofactor preference of PsXR gene was validated. Xylose fermentation was further studied with the strains developed with these strategies, and elevated xylose utilization rate was obtained in the scattered integration strain. These results proved that by positioning multiple genes on different chromosomes, fine-tuning of cellular metabolism could be achieved in recombinant S. cerevisiae.

Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy.

Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.

[Clinical application study of multiple small-diameter drilling combined with extracorporeal shock wave therapy (ESWT) under C-arm positioning in the treatment of early femoral head necrosis].

OBJECTIVE: To explore the therapeutic effect of multiple small diameter drilling combined with extracorporeal shock wave therapy (ESWT) under C-arm X-raylocalization in patients with early osteonecrosis of the femoral head (ONFH). METHODS: A total of 106 cases of early ONFH patients admitted from May 2015 to May 2017 were retrospectively selected as the study subjects. According to different treatment methods, the patients were divided into observation group and control group, 53 cases in each group. The observation group was treated with multiple small-diameter drilling combined with ESWT under C-arm positioning in the observation group, including 41 males and 12 females with an age of (45.85±6.01) years old (22 to 70 years old);and the control group was treated with ESWT, including 34 males and 19 females with an age of (45.12±5.83) years old(20 to 68 years old) in the control group. The modified Harris hip scores(mHHS), visual analog scale(VAS), hip flexion range, hip abduction and adduction range, ONFH area ratio and clinical efficacy were compared between twe groups before and after treatment. Kaplan-Meier method was used to draw a survival curve to compare the femoral head survival rate between two groups during the 3-year follow-up period after treatment. RESULTS: There were no complications such as poor wound healing and infection. All of 106 patients were followed up for 28 to 36 months with an average of (31.06±4.28) months. MHHS score, hip flexion range and hip abduction and adduction range in the observation group were increased from (63.85±5.42) scores, (23.79±2.21) °, (32.40±4.19) ° before treatment to (85.51±5.69) scores, (34.65±2.73)°, (43.32±5.71)° at 2 years after treatment, respectively(P<0.05). The above indicators in the control group increased from (64.73±5.64)°, (23.82±2.18)°, (32.45±4.13)° before treatment to (81.65±5.48) scores, (32.79±2.87)°, (39.75±5.68)°at two years after treatment, respectively(P<0.05). VAS score and ONFH area ratio in the observation group decreased from (5.76±1.41) scores and (35.07±4.96)% before treatment to (3.39±1.02) scores and (22.04±3.23)% at 2 years after treatment, respectively(P<0.05). The above indicatiors in control group decreased from (5.73±1.45) scores and (35.24±5.18)% before treatment to (4.43±1.21) scores and (28.32±3.76)% at 2 years after treatment, respectively(P<0.05), and the improvement in the observation group was significantly higher than that in the control group(P<0.05). At 3 years after treatment, the femoral head survival rate in the observation group was higher than that in the control group (P<0.05). CONCLUSION: Multiple small diameter drilling combined with ESWT under C-arm positioning can significantly improve the clinical symptoms of patients with early ONFH, relieve pain and improve clinical efficacy.

Glutathione-Scavenging Nanoparticle-Mediated PROTACs Delivery for Targeted Protein Degradation and Amplified Antitumor Effects.

PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin-proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano-PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano-PROTACs are developed by encapsulating PROTACs in glutathione (GSH)-responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano-PROTAC, nanoengineered BRD4 degrader ARV-771, improves BRD4 protein degradation and decreases the downstream oncogene c-Myc expression. Benefiting from the GSH-scavenging ability to amply the c-Myc-related ferroptosis and cell cycle arrest, this ARV@PDSA Nano-PROTACs strategy shows superior anti-tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano-PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

Nanosensitizer-mediated augmentation of sonodynamic therapy efficacy and antitumor immunity.

The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e-)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field.